Breast-ovarian cancer, familial, susceptibility to, 1

Summary

Breast-ovarian cancer, familial, susceptibility to, 1 (MONDO:0011450) is a cancer caused by BRCA1 (GenCC Definitive), with 25 cohort genes (19 CIViC-evidence somatic drivers; 6,263 ClinVar predisposition records). The dominant Reactome pathway is Impaired BRCA2 binding to PALB2 (9 cohort genes).

At a glance

• Classification: Cancer
• Causal gene: BRCA1 (GenCC Definitive)
• Cohort genes: 25
• ClinVar variants: 6,263

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	breast-ovarian cancer, familial, susceptibility to, 1
Mondo ID	MONDO:0011450
OMIM	604370
UMLS	C2676676
MedGen	382914
GARD	0027801
Is cancer (heuristic)	yes

Also known as: BRCA1 hereditary breast ovarian cancer syndrome · breast-ovarian cancer, familial, 1, multifactorial · breast-ovarian cancer, familial, susceptibility to, 1 · breast-ovarian cancer, familial, susceptibility to, type 1 · BROVCA1 · hereditary breast ovarian cancer syndrome caused by mutation in BRCA1

Data availability: 6,263 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › hereditary breast ovarian cancer syndrome › breast-ovarian cancer, familial, susceptibility to, 1

Related subtypes (1): breast-ovarian cancer, familial, susceptibility to, 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

214 pathogenic, 116 uncertain significance, 111 conflicting classifications of pathogenicity, 58 likely benign, 43 benign, 30 pathogenic/likely pathogenic, 16 benign/likely benign, 12 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
127340	NM_000051.4(ATM):c.1564_1565del (p.Glu522fs)	ATM	Pathogenic	reviewed by expert panel
127374	NM_000051.4(ATM):c.3802del (p.Glu1267_Val1268insTer)	ATM	Pathogenic	reviewed by expert panel
1049053	NM_007294.4(BRCA1):c.5296del (p.Ile1766fs)	BRCA1	Pathogenic	no assertion criteria provided
1049208	NM_007294.4(BRCA1):c.672del (p.Ala225fs)	BRCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1049236	NC_000017.11:g.43045676_43045803del	BRCA1	Pathogenic	no assertion criteria provided
1049239	NM_007294.4(BRCA1):c.1100del (p.Thr367fs)	BRCA1	Pathogenic	criteria provided, single submitter
1049380	NM_007294.4(BRCA1):c.81-1_134+2del	BRCA1	Pathogenic	no assertion criteria provided
1049561	NM_007294.4(BRCA1):c.5153-77_5193+4del	BRCA1	Pathogenic	no assertion criteria provided
1049567	NM_007294.4(BRCA1):c.2_80+4del	BRCA1	Pathogenic	no assertion criteria provided
1049576	NM_007294.4(BRCA1):c.5194-1_5277+2del	BRCA1	Pathogenic	no assertion criteria provided
1050520	NM_007294.4(BRCA1):c.5468-191_*2del	BRCA1	Pathogenic	no assertion criteria provided
1068970	NM_007294.4(BRCA1):c.166_169del (p.Lys56fs)	BRCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072154	NM_007294.4(BRCA1):c.1728_1731del (p.Lys576fs)	BRCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072882	NM_007294.4(BRCA1):c.915dup (p.Asn306Ter)	BRCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1174600	NM_007294.4(BRCA1):c.3359_3360insG (p.Val1120_Asn1121insTer)	BRCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1174602	NM_007294.4(BRCA1):c.4645_4646dup (p.Thr1550fs)	BRCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1174603	NM_007294.4(BRCA1):c.4821del (p.Ala1608fs)	BRCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1192261	NM_007294.4(BRCA1):c.2624del (p.Pro875fs)	BRCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
125452	NG_005905.2:g.139830_166277del	BRCA1	Pathogenic	no assertion criteria provided
125458	Single allele	BRCA1	Pathogenic	no assertion criteria provided
125459	Single allele	BRCA1	Pathogenic	no assertion criteria provided
125465	NM_007294.4(BRCA1):c.882del (p.Asp295fs)	BRCA1	Pathogenic	reviewed by expert panel
125466	Single allele	BRCA1	Pathogenic	no assertion criteria provided
125477	NM_007294.4(BRCA1):c.902_903insT (p.Lys301fs)	BRCA1	Pathogenic	reviewed by expert panel
125481	NM_007294.4(BRCA1):c.984_985insC (p.Asn329fs)	BRCA1	Pathogenic	reviewed by expert panel
125486	NM_007294.4(BRCA1):c.1101_1102insC (p.Glu368fs)	BRCA1	Pathogenic	reviewed by expert panel
125488	NM_007294.4(BRCA1):c.1129dup (p.Ser377fs)	BRCA1	Pathogenic	reviewed by expert panel
125491	NM_007294.4(BRCA1):c.19_47del (p.Arg7fs)	BRCA1	Pathogenic	reviewed by expert panel
125495	NM_007294.4(BRCA1):c.1356del (p.Glu453fs)	BRCA1	Pathogenic	reviewed by expert panel
125497	NM_007294.4(BRCA1):c.1387delinsGG (p.Lys463fs)	BRCA1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 116 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
BRCA1	LoF	BLCA,BRCA,MEL,OVT	CIViC #6
BRCA2	LoF	BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA	CIViC #7
TP53	LoF	ACC,ALL,AML,ANGS,ANSC,BCC,BL,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,EGC,ES,ESCA,ESCC,GB,GBC,GBM,GIST,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LNM,LUAD,LUSC,MBL,MEL,MLYM,MT,NBL,NETNOS,NHL,NPC,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PCM,PLMESO,PRAD,PRCC,PROSTATE,RCC,READ,SACA,SARCNOS,SCLC,SIC,SKCM,SKIN,SOFT_TISSUE,STAD,STOMACH,THYM,UCEC,UCS,UTUC,VULVA,WDTC,WT	CIViC #45
CHEK2	Act	BRCA	CIViC #8950
CDH1	LoF	BLCA,BRCA,CSCC,DLBCLNOS,ESCA,STAD	CIViC #888
BRIP1			CIViC #15955
PALB2	LoF	OVT	CIViC #15013
ABCC3			CIViC #6906
MLH1			CIViC #3532
MSH2			CIViC #3628
MSH6			CIViC #2478
NF1	LoF	ACC,ALL,AML,ANGS,BLCA,BRCA,CCRCC,CHOL,CLLSLL,COADREAD,GB,GBM,GIST,HCC,HNSC,LGGNOS,LMS,LUAD,LUNG,LUSC,MEL,NBL,NSCLC,OVT,PAST,PGNG,PLMESO,RMS,SKCM,SOFT_TISSUE,STAD,THYM,UCS	CIViC #3867
ATM	LoF	BLCA,BRCA,CCRCC,CHOL,CLLSLL,COAD,COADREAD,ESCA,HCC,LUAD,LUSC,MEL,NSCLC,PAAD,PANCREAS,PANET,PCM,PLMESO,PRAD,PROSTATE,STAD,UCEC,UTUC,WDTC	CIViC #69
PMS2	ambiguous	HCC	CIViC #4371
PTEN	LoF	ANGS,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,COADREAD,CSCC,ESCA,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LUAD,LUSC,MBL,MEL,MT,NSCLC,OVT,PANET,PAST,PRAD,PRCC,PROSTATE,RCC,SCLC,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,WDTC	CIViC #41
RAD50	Act	GBM	CIViC #8032
RAD51C			CIViC #4762
RAD51D			CIViC #4765
RET	Act	ANGS,MEL,NSCLC,PGNG,SOFT_TISSUE,WDTC	CIViC #42

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BRCA1	Definitive	Autosomal dominant	breast-ovarian cancer, familial, susceptibility to, 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRCA1	Orphanet:1331	Familial prostate cancer
BRCA1	Orphanet:1333	Familial pancreatic carcinoma
BRCA1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA1	Orphanet:168829	Primary peritoneal carcinoma
BRCA1	Orphanet:227535	Hereditary breast cancer
BRCA1	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA1	Orphanet:694963	Inflammatory breast cancer
BRCA1	Orphanet:70567	Cholangiocarcinoma
BRCA1	Orphanet:84	Fanconi anemia
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
CHEK2	Orphanet:1331	Familial prostate cancer
CHEK2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
CHEK2	Orphanet:440437	Familial colorectal cancer Type X
CHEK2	Orphanet:524	Li-Fraumeni syndrome
CHEK2	Orphanet:668	Osteosarcoma
CDH1	Orphanet:1331	Familial prostate cancer
CDH1	Orphanet:199306	Cleft lip/palate
CDH1	Orphanet:1997	Blepharo-cheilo-odontic syndrome
CDH1	Orphanet:227535	Hereditary breast cancer

Cohort genes → proteins

25 cohort genes, 24 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	25

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRCA1	HGNC:1100	ENSG00000012048	P38398	Breast cancer type 1 susceptibility protein	gencc,clinvar
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	clinvar
NISCH	HGNC:18006	ENSG00000010322	Q9Y2I1	Nischarin	clinvar
KRTAP4-9	HGNC:18910	ENSG00000212722	Q9BYQ8	Keratin-associated protein 4-9	clinvar
BRIP1	HGNC:20473	ENSG00000136492	Q9BX63	Fanconi anemia group J protein	clinvar
NBR2	HGNC:20691	ENSG00000198496		neighbor of BRCA1 lncRNA 2	clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar
TMEM106A	HGNC:28288	ENSG00000184988	Q96A25	Transmembrane protein 106A	clinvar
C11orf65	HGNC:28519	ENSG00000166323	Q8NCR3	Protein MFI	clinvar
ABCC3	HGNC:54	ENSG00000108846	O15438	ATP-binding cassette sub-family C member 3	clinvar
MLH1	HGNC:7127	ENSG00000076242	P40692	DNA mismatch repair protein Mlh1	clinvar
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	clinvar
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	clinvar
NBN	HGNC:7652	ENSG00000104320	O60934	Nibrin	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
PMS2	HGNC:9122	ENSG00000122512	P54278	Mismatch repair endonuclease PMS2	clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar
RAD50	HGNC:9816	ENSG00000113522	Q92878	DNA repair protein RAD50	clinvar
RAD51C	HGNC:9820	ENSG00000108384	O43502	DNA repair protein RAD51 homolog 3	clinvar
RAD51D	HGNC:9823	ENSG00000185379	O75771	DNA repair protein RAD51 homolog 4	clinvar
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRCA1	Breast cancer type 1 susceptibility protein	E3 ubiquitin-protein ligase that specifically mediates the formation of ‘Lys-6’-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.
NISCH	Nischarin	Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling.
KRTAP4-9	Keratin-associated protein 4-9	In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated proteins (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through t…
BRIP1	Fanconi anemia group J protein	DNA-dependent ATPase and 5’-3’ DNA helicase required for the maintenance of chromosomal stability.
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
TMEM106A	Transmembrane protein 106A	Activates macrophages and polarizes them into M1-like macrophages through the activation of the MAPK and NF-kappaB signaling pathway.
C11orf65	Protein MFI	Acts as an inhibitor of mitochondrial fission.
ABCC3	ATP-binding cassette sub-family C member 3	ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes.
MLH1	DNA mismatch repair protein Mlh1	Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR).
MSH2	DNA mismatch repair protein Msh2	Component of the post-replicative DNA mismatch repair system (MMR).
MSH6	DNA mismatch repair protein Msh6	Component of the post-replicative DNA mismatch repair system (MMR).
NBN	Nibrin	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.
PMS2	Mismatch repair endonuclease PMS2	Component of the post-replicative DNA mismatch repair system (MMR).
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
RAD50	DNA repair protein RAD50	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
RAD51C	DNA repair protein RAD51 homolog 3	Essential for the homologous recombination (HR) pathway of DNA repair.
RAD51D	DNA repair protein RAD51 homolog 4	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…

Protein-family classification

Druggable: 6 · Difficult: 3 · Unknown: 16 · Druggable fraction: 0.24

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	3	3.3×	0.418
Phosphatase	1	3.4×	0.484
Transporter	1	3.1×	0.484
Other/Unknown	16	1.1×	0.484
Scaffold/PPI	1	0.7×	0.887
Transcription factor	2	0.7×	0.887
Enzyme (other)	1	0.5×	0.887

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRCA1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, BRCA1
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
NISCH	Other/Unknown	no		Leu-rich_rpt, PX_dom, LRR_dom_sf
KRTAP4-9	Other/Unknown	no		KAP
BRIP1	Enzyme (other)	yes	3.6.4.12	Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
NBR2	Other/Unknown	no
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
TMEM106A	Other/Unknown	no		TMEM106, TMEM106_C, TMEM106_N
C11orf65	Other/Unknown	no
ABCC3	Transporter	yes	7.6.2.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, MRP
MLH1	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
MSH2	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
MSH6	Other/Unknown	no		PWWP_dom, DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N
NBN	Other/Unknown	no		FHA_dom, BRCT_dom, SMAD_FHA_dom_sf
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PMS2	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
RAD50	Other/Unknown	no		Rad50_eukaryotes, Zn_hook_RAD50, P-loop_NTPase
RAD51C	Other/Unknown	no		Rad51_C, DNA_recomb/repair_RecA-like, RecA_ATP-bd
RAD51D	Other/Unknown	no		AAA+_ATPase, Rad51_C, DNA_recomb/repair_RecA-like
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom

Expression context

Cohort genes with no expression data: 0.

22 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	25
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	6
ventricular zone	6
primordial germ cell in gonad	5
calcaneal tendon	4
secondary oocyte	3
oocyte	3
sperm	3
colonic epithelium	3
ganglionic eminence	2
buccal mucosa cell	2
right testis	2
corpus callosum	2
tendon of biceps brachii	1
lower esophagus mucosa	1
esophagus squamous epithelium	1
gingival epithelium	1
jejunal mucosa	1
cerebellar hemisphere	1
middle temporal gyrus	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRCA1	208	ubiquitous	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium
NISCH	293	ubiquitous	marker	middle temporal gyrus, right hemisphere of cerebellum, cerebellar hemisphere
KRTAP4-9	27		yes	sural nerve, skin of abdomen, zone of skin
BRIP1	181	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
NBR2	214	ubiquitous	marker	oviduct epithelium, mucosa of transverse colon, primordial germ cell in gonad
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
TMEM106A	228	ubiquitous	marker	buccal mucosa cell, renal medulla, pylorus
C11orf65	163	ubiquitous	marker	sperm, left testis, right testis
ABCC3	231	ubiquitous	marker	pancreatic ductal cell, right adrenal gland, right adrenal gland cortex
MLH1	296	ubiquitous	marker	tibialis anterior, skeletal muscle tissue of rectus abdominis, deltoid
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
MSH6	293	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
NBN	299	ubiquitous	marker	endometrium epithelium, mammary duct, cauda epididymis
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PMS2	143	ubiquitous	marker	thymus, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
RAD50	134	ubiquitous	marker	corpus callosum, calcaneal tendon, colonic epithelium
RAD51C	281	ubiquitous	marker	primordial germ cell in gonad, right testis, male germ line stem cell (sensu Vertebrata) in testis
RAD51D	187	ubiquitous	yes	sperm, male germ cell, oocyte
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta

Protein interactions among cohort

Intra-cohort edges: 64.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
PTEN	11,626
BRCA1	9,064
CDH1	8,738
ATM	7,383
PALB2	5,641
NF1	5,540
BRCA2	4,839
CHEK2	4,795
MSH2	4,537

Intra-cohort edges

A	B	Sources
ABCC3	MLH1	intact
ATM	BRCA1	string_interaction
ATM	BRCA2	string_interaction
ATM	CHEK2	string_interaction
ATM	MLH1	string_interaction
ATM	MSH2	string_interaction
ATM	MSH6	string_interaction
ATM	NBN	biogrid_interaction, string_interaction
ATM	RAD50	string_interaction
ATM	RAD51D	string_interaction
ATM	TP53	biogrid_interaction, string_interaction
BRCA1	BRCA2	string_interaction
BRCA1	BRIP1	biogrid_interaction, intact, string_interaction
BRCA1	CHEK2	string_interaction
BRCA1	MLH1	string_interaction
BRCA1	MSH2	string_interaction
BRCA1	MSH6	string_interaction
BRCA1	NBN	string_interaction
BRCA1	NF1	string_interaction
BRCA1	PALB2	biogrid_interaction, intact, string_interaction
BRCA1	PMS2	string_interaction
BRCA1	RAD50	biogrid_interaction, string_interaction
BRCA1	RAD51C	string_interaction
BRCA1	RAD51D	string_interaction
BRCA1	TP53	string_interaction
BRCA2	BRIP1	string_interaction
BRCA2	CHEK2	string_interaction
BRCA2	MLH1	string_interaction
BRCA2	MSH2	string_interaction
BRCA2	MSH6	string_interaction
BRCA2	NBN	string_interaction
BRCA2	PALB2	biogrid_interaction, intact, string_interaction
BRCA2	PMS2	string_interaction
BRCA2	RAD51C	biogrid_interaction, string_interaction
BRCA2	RAD51D	string_interaction
BRCA2	TP53	string_interaction
BRIP1	MLH1	intact, string_interaction
BRIP1	PALB2	string_interaction
BRIP1	PMS2	biogrid_interaction, intact
CDH1	PTEN	string_interaction
CHEK2	MSH6	string_interaction
CHEK2	NBN	string_interaction
CHEK2	PALB2	string_interaction
CHEK2	RAD51D	string_interaction
CHEK2	TP53	intact, string_interaction
MLH1	MSH2	string_interaction
MLH1	MSH6	string_interaction
MLH1	NBN	string_interaction
MLH1	PMS2	biogrid_interaction, intact, string_interaction
MLH1	RAD51D	string_interaction

Structural data

PDB: 21 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
CHEK2	O96017	38
RET	P07949	34
BRCA1	P38398	33
MSH2	P43246	30
NF1	P21359	26
CDH1	P12830	22
RAD51C	O43502	17
RAD51D	O75771	17
BRCA2	P51587	14
ATM	Q13315	14
PTEN	P60484	12
PMS2	P54278	9
MSH6	P52701	8
MLH1	P40692	7
NBN	O60934	7
RAD50	Q92878	6
PALB2	Q86YC2	4
ABCC3	O15438	4
BRIP1	Q9BX63	3
NISCH	Q9Y2I1	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM106A	Q96A25	76.10
C11orf65	Q8NCR3	74.69
KRTAP4-9	Q9BYQ8	36.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 205. Enrichment computed across 25 evidence-associated genes (22 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 22 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Impaired BRCA2 binding to PALB2	9	186.9×	1e-17	BRCA1, BRCA2, BRIP1, PALB2, NBN, ATM, RAD50, RAD51C (+1 more)
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	9	173.0×	1e-17	BRCA1, BRCA2, BRIP1, PALB2, NBN, ATM, RAD50, RAD51C (+1 more)
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	9	173.0×	1e-17	BRCA1, BRCA2, BRIP1, PALB2, NBN, ATM, RAD50, RAD51C (+1 more)
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	9	173.0×	1e-17	BRCA1, BRCA2, BRIP1, PALB2, NBN, ATM, RAD50, RAD51C (+1 more)
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	9	161.1×	2e-17	BRCA1, BRCA2, BRIP1, PALB2, NBN, ATM, RAD50, RAD51C (+1 more)
Homologous DNA Pairing and Strand Exchange	9	155.7×	3e-17	BRCA1, BRCA2, BRIP1, PALB2, NBN, ATM, RAD50, RAD51C (+1 more)
Resolution of D-loop Structures through Holliday Junction Intermediates	9	122.9×	3e-16	BRCA1, BRCA2, BRIP1, PALB2, NBN, ATM, RAD50, RAD51C (+1 more)
HDR through Homologous Recombination (HRR)	9	77.9×	2e-14	BRCA1, BRCA2, BRIP1, PALB2, NBN, ATM, RAD50, RAD51C (+1 more)
Diseases of DNA repair	7	181.7×	6e-14	BRCA1, BRCA2, MLH1, MSH2, MSH6, NBN, ATM
Presynaptic phase of homologous DNA pairing and strand exchange	8	98.9×	1e-13	BRCA1, BRCA2, BRIP1, NBN, ATM, RAD50, RAD51C, RAD51D
TP53 Regulates Transcription of DNA Repair Genes	7	57.7×	3e-10	BRCA1, TP53, MLH1, MSH2, ATM, PMS2, RAD51D
Impaired BRCA2 binding to RAD51	6	84.2×	9e-10	BRCA1, BRCA2, BRIP1, NBN, ATM, RAD50
Meiotic recombination	7	41.3×	3e-09	BRCA1, BRCA2, MLH1, NBN, ATM, RAD50, RAD51C
G2/M DNA damage checkpoint	7	38.2×	5e-09	BRCA1, TP53, CHEK2, BRIP1, NBN, ATM, RAD50
Regulation of TP53 Activity through Phosphorylation	7	37.5×	5e-09	BRCA1, TP53, CHEK2, BRIP1, NBN, ATM, RAD50
DNA Repair	7	31.3×	2e-08	BRCA1, BRCA2, MLH1, MSH2, MSH6, NBN, ATM
Defective homologous recombination repair (HRR) due to PALB2 loss of function	4	173.0×	6e-08	BRCA1, BRCA2, NBN, ATM
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	6	39.9×	7e-08	BRCA1, TP53, CHEK2, NBN, ATM, RAD50
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	4	148.3×	9e-08	MLH1, MSH2, MSH6, PMS2
Diseases of DNA Double-Strand Break Repair	4	148.3×	9e-08	BRCA1, BRCA2, NBN, ATM
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	4	148.3×	9e-08	BRCA1, BRCA2, NBN, ATM
HDR through Single Strand Annealing (SSA)	5	66.5×	9e-08	BRCA1, BRIP1, NBN, ATM, RAD50
Meiosis	5	64.9×	9e-08	BRCA1, BRCA2, MLH1, NBN, ATM
Mismatch Repair	3	389.3×	2e-07	MLH1, MSH2, MSH6
Diseases of Mismatch Repair (MMR)	3	389.3×	2e-07	MLH1, MSH2, MSH6
Resolution of D-Loop Structures	4	115.3×	2e-07	BRCA1, BRCA2, NBN, ATM
Reproduction	5	43.3×	6e-07	BRCA1, BRCA2, MLH1, NBN, ATM
Sensing of DNA Double Strand Breaks	3	259.6×	9e-07	NBN, ATM, RAD50
Homology Directed Repair	4	56.1×	4e-06	BRCA1, BRCA2, NBN, ATM
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	4	56.1×	4e-06	BRCA1, BRCA2, NBN, ATM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 24 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
double-strand break repair	9	76.1×	7e-13	BRCA1, BRCA2, TP53, CHEK2, BRIP1, MSH2, NBN, ATM (+1 more)
double-strand break repair via homologous recombination	8	52.0×	4e-10	BRCA1, BRCA2, PALB2, NBN, ATM, RAD50, RAD51C, RAD51D
telomere maintenance via recombination	4	255.3×	2e-07	BRCA2, RAD50, RAD51C, RAD51D
homologous recombination	4	234.1×	2e-07	BRCA1, BRIP1, NBN, RAD50
somatic hypermutation of immunoglobulin genes	4	175.5×	5e-07	MLH1, MSH2, MSH6, PMS2
DNA damage response, signal transduction by p53 class mediator	5	74.7×	5e-07	BRCA2, TP53, CHEK2, NBN, ATM
somatic recombination of immunoglobulin gene segments	3	526.6×	6e-07	MSH2, MSH6, PMS2
intrinsic apoptotic signaling pathway in response to DNA damage	5	67.5×	6e-07	BRCA1, CHEK2, MLH1, MSH6, ATM
isotype switching	4	140.4×	8e-07	MLH1, MSH2, MSH6, NBN
negative regulation of telomere capping	3	421.3×	1e-06	NBN, ATM, RAD50
mismatch repair	4	108.0×	2e-06	MLH1, MSH2, MSH6, PMS2
positive regulation of isotype switching to IgA isotypes	3	351.1×	2e-06	MLH1, MSH2, PMS2
DNA repair	7	18.6×	2e-06	BRCA1, BRIP1, MSH2, MSH6, RAD50, RAD51C, RAD51D
reciprocal meiotic recombination	4	93.6×	3e-06	ATM, RAD50, RAD51C, RAD51D
DNA strand resection involved in replication fork processing	3	263.3×	4e-06	BRCA1, NBN, RAD50
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	4	82.6×	4e-06	BRCA2, TP53, CHEK2, MSH2
determination of adult lifespan	4	72.0×	7e-06	TP53, MSH2, MSH6, ATM
DNA double-strand break processing	3	191.5×	1e-05	NBN, ATM, RAD50
positive regulation of isotype switching to IgG isotypes	3	191.5×	1e-05	MLH1, MSH2, PMS2
DNA damage checkpoint signaling	4	65.3×	1e-05	CHEK2, BRIP1, NBN, ATM
replicative senescence	3	123.9×	4e-05	TP53, CHEK2, ATM
telomere maintenance	4	44.6×	4e-05	NBN, ATM, RAD50, RAD51D
response to X-ray	3	110.9×	5e-05	BRCA2, TP53, MSH2
mitotic G2/M transition checkpoint	3	100.3×	7e-05	BRCA1, NBN, RAD50
cellular response to gamma radiation	3	75.2×	2e-04	TP53, CHEK2, ATM
telomeric 3’ overhang formation	2	351.1×	2e-04	NBN, RAD50
regulation of cell cycle	5	15.5×	3e-04	BRCA1, TP53, NBN, ATM, RAD51D
cellular response to indole-3-methanol	2	280.9×	3e-04	BRCA1, CDH1
mitotic G2 DNA damage checkpoint signaling	3	55.4×	3e-04	BRCA1, NBN, ATM
cellular response to ionizing radiation	3	51.4×	4e-04	BRCA1, BRCA2, TP53

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 9 · Undrugged: 16

Druggability breadth: 14 of 25 evidence-associated genes (56%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BRCA1	RIBOFLAVIN
TP53	NITROFURANTOIN
CHEK2	NERATINIB
NISCH	TIZANIDINE
ABCC3	TELMISARTAN
ATM	AMIODARONE HYDROCHLORIDE
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
RET	135	4
ABCC3	43	4
ATM	35	4
CHEK2	30	4
NISCH	15	4
BRCA1	12	4
MSH6	1	2
RAD50	1	2
BRCA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1, TP53
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	ATM, BRCA1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	ATM, TP53
FURAZOLIDONE	4	ATM, TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
CHEK2	690	Binding:687, Functional:2, ADMET:1
ATM	240	Binding:233, Functional:5, ADMET:2
NISCH	38	Binding:38
ABCC3	37	Binding:21, ADMET:16
CDH1	18	Binding:18
BRCA1	13	Binding:9, Functional:4
MSH6	10	Binding:10
MSH2	9	Binding:9
PTEN	8	Binding:8
RAD50	7	Binding:7
NBN	2	Binding:2
PMS2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRCA1	2.3.2.27	RING-type E3 ubiquitin transferase
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
BRIP1	3.6.4.12	DNA helicase
ABCC3	7.6.2.3	ABC-type glutathione-S-conjugate transporter
ATM	2.7.11.1	non-specific serine/threonine protein kinase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TP53	869
CHEK2	690
ATM	240
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 25; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

30 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1, TP53
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	ATM, BRCA1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	ATM, TP53
FURAZOLIDONE	4	ATM, TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	BRCA1, TP53, CHEK2, NISCH, ABCC3, ATM, RET
B	Phased (≥1) drug, not yet approved	2	MSH6, RAD50
C	Druggable family + PDB, no drug	2	BRIP1, PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	14	BRCA2, CDH1, KRTAP4-9, NBR2, PALB2, TMEM106A, C11orf65, MLH1, MSH2, NBN (+4 more)

Undrugged target profiles

16 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BRCA2	0	BRCA1
BRIP1	0	BRCA1
PALB2	0	BRCA1
MLH1	0	MSH6
NBN	2	RAD50, ATM, BRCA1
PMS2	1	MSH6
PTEN	8	TP53
RAD51D	0	BRCA1
CDH1	18	—
KRTAP4-9	0	—
NBR2	0	—
TMEM106A	0	—
C11orf65	0	—
MSH2	9	—
NF1	0	—
RAD51C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.