Breast-ovarian cancer, familial, susceptibility to, 2

disease

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Also known as BRCA2 hereditary breast ovarian cancer syndromebreast-ovarian cancer, familial, 2breast-ovarian cancer, familial, susceptibility to, type 2BROVCA2hereditary breast ovarian cancer syndrome caused by mutation in BRCA2

Summary

Breast-ovarian cancer, familial, susceptibility to, 2 (MONDO:0012933) is a cancer caused by BRCA2 (GenCC Definitive), with 20 cohort genes (15 CIViC-evidence somatic drivers; 7,923 ClinVar predisposition records). The dominant Reactome pathway is Impaired BRCA2 binding to PALB2 (9 cohort genes).

At a glance

Classification: Cancer
Causal gene: BRCA2 (GenCC Definitive)
Cohort genes: 20
ClinVar variants: 7,923

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	breast-ovarian cancer, familial, susceptibility to, 2
Mondo ID	MONDO:0012933
OMIM	612555
UMLS	C2675520
MedGen	382625
GARD	0027821
Is cancer (heuristic)	yes

Also known as: BRCA2 hereditary breast ovarian cancer syndrome · breast-ovarian cancer, familial, 2 · breast-ovarian cancer, familial, susceptibility to, 2 · breast-ovarian cancer, familial, susceptibility to, type 2 · BROVCA2 · hereditary breast ovarian cancer syndrome caused by mutation in BRCA2

Data availability: 7,923 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, 2

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

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:

219 conflicting classifications of pathogenicity, 181 pathogenic, 77 uncertain significance, 62 likely benign, 36 benign, 11 pathogenic/likely pathogenic, 8 benign/likely benign, 4 likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012160	NM_000059.4(BRCA2):c.5362del (p.Ser1788fs)	BRCA2	Pathogenic	criteria provided, single submitter
1067980	NM_000059.4(BRCA2):c.-39-1G>C	BRCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070128	NM_000059.4(BRCA2):c.3716_3717del (p.Lys1239fs)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1070335	NM_000059.4(BRCA2):c.3472G>T (p.Glu1158Ter)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1070336	NM_000059.4(BRCA2):c.7495del (p.Gln2499fs)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1071769	NM_000059.4(BRCA2):c.5622dup (p.Lys1875Ter)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1072364	NM_000059.4(BRCA2):c.724A>T (p.Lys242Ter)	BRCA2	Pathogenic	criteria provided, single submitter
1072657	NM_000059.4(BRCA2):c.2809C>T (p.Gln937Ter)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1073562	NM_000059.4(BRCA2):c.5985del (p.Asn1995fs)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1073855	NM_000059.4(BRCA2):c.5150_5226delinsTACTTAATACTTATTAAGTATTA (p.Glu1717_Asn1742delinsValLeuAsnThrTyrTer)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1075832	NM_000059.4(BRCA2):c.444T>A (p.Cys148Ter)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1076700	NM_000059.4(BRCA2):c.9699T>A (p.Cys3233Ter)	BRCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1170996	NM_000059.4(BRCA2):c.8696_8712del (p.Gln2899fs)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1174606	NM_000059.4(BRCA2):c.93_97del (p.Trp31_Glu33delinsTer)	BRCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1195872	NM_000059.4(BRCA2):c.1507A>T (p.Lys503Ter)	BRCA2	Pathogenic	criteria provided, single submitter
125921	BRCA2: exon 2 deletion	BRCA2	Pathogenic	no assertion criteria provided
125928	NM_000059.4(BRCA2):c.891_899delinsGATACTTCAG (p.Thr298fs)	BRCA2	Pathogenic	reviewed by expert panel
125931	NM_000059.4(BRCA2):c.995_996insG (p.Ile332fs)	BRCA2	Pathogenic	reviewed by expert panel
125936	NM_000059.4(BRCA2):c.1190_1191insTTAG (p.Gln397delinsHisTer)	BRCA2	Pathogenic	reviewed by expert panel
125937	NM_000059.4(BRCA2):c.1231del (p.Ile411fs)	BRCA2	Pathogenic	reviewed by expert panel
125942	NM_000059.4(BRCA2):c.1362dup (p.Ser455fs)	BRCA2	Pathogenic	reviewed by expert panel
125945	NM_000059.4(BRCA2):c.1408dup (p.Glu470fs)	BRCA2	Pathogenic	reviewed by expert panel
125948	NM_000059.4(BRCA2):c.1542dup (p.Thr515fs)	BRCA2	Pathogenic	reviewed by expert panel
125949	NM_000059.4(BRCA2):c.1608dup (p.Glu537Ter)	BRCA2	Pathogenic	reviewed by expert panel
125951	NM_000059.4(BRCA2):c.1648dup (p.Glu550fs)	BRCA2	Pathogenic	reviewed by expert panel
125952	NM_000059.3(BRCA2):c.1668_1671delTTTAins3	BRCA2	Pathogenic	no assertion criteria provided
125970	NM_000059.4(BRCA2):c.1854_1855insA (p.Gln619fs)	BRCA2	Pathogenic	reviewed by expert panel
125978	NM_000059.4(BRCA2):c.2212dup (p.Cys738fs)	BRCA2	Pathogenic	reviewed by expert panel
125980	NM_000059.4(BRCA2):c.37_38insT (p.Glu13fs)	BRCA2	Pathogenic	reviewed by expert panel
125981	NM_000059.4(BRCA2):c.2439dup (p.Pro814fs)	BRCA2	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 96 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
BRCA2	LoF	BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA	CIViC #7
BRCA1	LoF	BLCA,BRCA,MEL,OVT	CIViC #6
STK11	LoF	ANSC,CEAD,CESC,CHOL,LUAD,NSCLC,WDTC	CIViC #5534
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
KLLN			CIViC #32083
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
BARD1	Act	PRAD	CIViC #549
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

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
BRCA2	Definitive	Autosomal dominant	breast-ovarian cancer, familial, susceptibility to, 2	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
STK11	Orphanet:2869	Peutz-Jeghers syndrome
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

Cohort genes → proteins

20 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	20

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	gencc,clinvar
BRCA1	HGNC:1100	ENSG00000012048	P38398	Breast cancer type 1 susceptibility protein	clinvar
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	clinvar
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar
CD68	HGNC:1693	ENSG00000129226	P34810	Macrosialin	clinvar
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	clinvar
BRIP1	HGNC:20473	ENSG00000136492	Q9BX63	Fanconi anemia group J protein	clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar
TMEM132E	HGNC:26991	ENSG00000181291	Q6IEE7	Transmembrane protein 132E	clinvar
GPSM2	HGNC:29501	ENSG00000121957	P81274	G-protein-signaling modulator 2	clinvar
KLLN	HGNC:37212	ENSG00000227268	B2CW77	Killin	clinvar
RNFT1-DT	HGNC:51346	ENSG00000267302		RNFT1 divergent transcript	clinvar
NBN	HGNC:7652	ENSG00000104320	O60934	Nibrin	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
PMS2	HGNC:9122	ENSG00000122512	P54278	Mismatch repair endonuclease PMS2	clinvar
BARD1	HGNC:952	ENSG00000138376	Q99728	BRCA1-associated RING domain protein 1	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

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
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.
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…
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.
CD68	Macrosialin	Could play a role in phagocytic activities of tissue macrophages, both in intracellular lysosomal metabolism and extracellular cell-cell and cell-pathogen interactions.
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.
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.
TMEM132E	Transmembrane protein 132E	Required for normal inner ear hair cell function and hearing.
GPSM2	G-protein-signaling modulator 2	Plays an important role in mitotic spindle pole organization via its interaction with NUMA1.
KLLN	Killin	DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis.
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.
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).
BARD1	BRCA1-associated RING domain protein 1	E3 ubiquitin-protein ligase.
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.

Protein-family classification

Druggable: 5 · Difficult: 4 · Unknown: 11 · Druggable fraction: 0.25

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	4.2×	0.202
Phosphatase	1	4.2×	0.640
Transcription factor	3	1.2×	0.825
Other/Unknown	11	1.0×	0.825
Scaffold/PPI	1	0.9×	0.825
Enzyme (other)	1	0.6×	0.825

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
BRCA1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, BRCA1
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
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
CD68	Other/Unknown	no		Lysosome-assoc_membr_glycop, LAMP_CS, Lamp2-like_luminal
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
BRIP1	Enzyme (other)	yes	3.6.4.12	Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
TMEM132E	Other/Unknown	no		TMEM132, TMEM132_N, TMEM132_C
GPSM2	Other/Unknown	no		GoLoco_motif, TPR-like_helical_dom_sf, TPR_rpt
KLLN	Other/Unknown	no
RNFT1-DT	Other/Unknown	no
NBN	Other/Unknown	no		FHA_dom, BRCT_dom, SMAD_FHA_dom_sf
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
BARD1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, Ankyrin_rpt
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

Expression context

Cohort genes with no expression data: 0.

17 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)	20
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	8
ventricular zone	4
primordial germ cell in gonad	4
secondary oocyte	3
calcaneal tendon	3
right testis	2
buccal mucosa cell	2
oocyte	2
colonic epithelium	2
corpus callosum	2
hindlimb stylopod muscle	1
left testis	1
ganglionic eminence	1
tendon of biceps brachii	1
lower esophagus mucosa	1
granulocyte	1
leukocyte	1
monocyte	1
esophagus squamous epithelium	1
gingival epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
BRCA1	208	ubiquitous	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
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
CD68	141	ubiquitous	marker	monocyte, leukocyte, granulocyte
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium
BRIP1	181	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
TMEM132E	169	tissue_specific	yes	kidney epithelium, right hemisphere of cerebellum, cerebellar hemisphere
GPSM2	287	ubiquitous	marker	tibia, buccal mucosa cell, amniotic fluid
KLLN	149		marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
RNFT1-DT	133	broad	yes	quadriceps femoris, male germ line stem cell (sensu Vertebrata) in testis, cerebellar vermis
NBN	299	ubiquitous	marker	endometrium epithelium, mammary duct, cauda epididymis
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
BARD1	271	ubiquitous	marker	secondary oocyte, oocyte, tongue squamous epithelium
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

Protein interactions among cohort

Intra-cohort edges: 45.

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
STK11	5,146
BRCA2	4,839
CHEK2	4,795
BARD1	4,230

Intra-cohort edges

A	B	Sources
ATM	BARD1	string_interaction
ATM	BRCA1	string_interaction
ATM	BRCA2	string_interaction
ATM	CHEK2	string_interaction
ATM	NBN	biogrid_interaction, string_interaction
ATM	RAD50	string_interaction
ATM	STK11	string_interaction
ATM	TP53	biogrid_interaction, string_interaction
BARD1	BRCA1	biogrid_interaction, intact, string_interaction
BARD1	BRCA2	string_interaction
BARD1	BRIP1	biogrid_interaction
BARD1	CHEK2	string_interaction
BARD1	PALB2	string_interaction
BARD1	RAD51C	string_interaction
BRCA1	BRCA2	string_interaction
BRCA1	BRIP1	biogrid_interaction, intact, string_interaction
BRCA1	CHEK2	string_interaction
BRCA1	NBN	string_interaction
BRCA1	PALB2	biogrid_interaction, intact, string_interaction
BRCA1	PMS2	string_interaction
BRCA1	RAD50	biogrid_interaction, string_interaction
BRCA1	RAD51C	string_interaction
BRCA1	TP53	string_interaction
BRCA2	BRIP1	string_interaction
BRCA2	CHEK2	string_interaction
BRCA2	NBN	string_interaction
BRCA2	PALB2	biogrid_interaction, intact, string_interaction
BRCA2	PMS2	string_interaction
BRCA2	RAD51C	biogrid_interaction, string_interaction
BRCA2	STK11	string_interaction
BRCA2	TP53	string_interaction
BRIP1	PALB2	string_interaction
BRIP1	PMS2	biogrid_interaction, intact
CDH1	PTEN	string_interaction
CHEK2	NBN	string_interaction
CHEK2	PALB2	string_interaction
CHEK2	TP53	intact, string_interaction
KLLN	PTEN	string_interaction
KLLN	TP53	string_interaction
NBN	RAD50	biogrid_interaction, intact, string_interaction
PALB2	RAD51C	biogrid_interaction, intact, string_interaction
PALB2	STK11	string_interaction
PTEN	STK11	string_interaction
PTEN	TP53	string_interaction
STK11	TP53	string_interaction

Structural data

PDB: 16 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
CHEK2	O96017	38
BRCA1	P38398	33
CDH1	P12830	22
RAD51C	O43502	17
BRCA2	P51587	14
ATM	Q13315	14
PTEN	P60484	12
BARD1	Q99728	11
PMS2	P54278	9
GPSM2	P81274	7
NBN	O60934	7
RAD50	Q92878	6
STK11	Q15831	4
PALB2	Q86YC2	4
BRIP1	Q9BX63	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CD68	P34810	74.23
TMEM132E	Q6IEE7	72.44
KLLN	B2CW77	51.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 184. Enrichment computed across 20 evidence-associated genes (17 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 17 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	241.8×	6e-19	BRCA2, BRCA1, BRIP1, PALB2, NBN, ATM, BARD1, RAD50 (+1 more)
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	9	223.9×	6e-19	BRCA2, BRCA1, BRIP1, PALB2, NBN, ATM, BARD1, RAD50 (+1 more)
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	9	223.9×	6e-19	BRCA2, BRCA1, BRIP1, PALB2, NBN, ATM, BARD1, RAD50 (+1 more)
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	9	223.9×	6e-19	BRCA2, BRCA1, BRIP1, PALB2, NBN, ATM, BARD1, RAD50 (+1 more)
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	9	208.5×	1e-18	BRCA2, BRCA1, BRIP1, PALB2, NBN, ATM, BARD1, RAD50 (+1 more)
Homologous DNA Pairing and Strand Exchange	9	201.5×	1e-18	BRCA2, BRCA1, BRIP1, PALB2, NBN, ATM, BARD1, RAD50 (+1 more)
Resolution of D-loop Structures through Holliday Junction Intermediates	9	159.1×	1e-17	BRCA2, BRCA1, BRIP1, PALB2, NBN, ATM, BARD1, RAD50 (+1 more)
HDR through Homologous Recombination (HRR)	9	100.8×	9e-16	BRCA2, BRCA1, BRIP1, PALB2, NBN, ATM, BARD1, RAD50 (+1 more)
Presynaptic phase of homologous DNA pairing and strand exchange	8	128.0×	8e-15	BRCA2, BRCA1, BRIP1, NBN, ATM, BARD1, RAD50, RAD51C
Regulation of TP53 Activity through Phosphorylation	9	62.3×	7e-14	BRCA1, STK11, TP53, CHEK2, BRIP1, NBN, ATM, BARD1 (+1 more)
Impaired BRCA2 binding to RAD51	7	127.1×	7e-13	BRCA2, BRCA1, BRIP1, NBN, ATM, BARD1, RAD50
G2/M DNA damage checkpoint	8	56.6×	6e-12	BRCA1, TP53, CHEK2, BRIP1, NBN, ATM, BARD1, RAD50
Defective homologous recombination repair (HRR) due to PALB2 loss of function	5	279.9×	4e-11	BRCA2, BRCA1, NBN, ATM, BARD1
Diseases of DNA Double-Strand Break Repair	5	239.9×	9e-11	BRCA2, BRCA1, NBN, ATM, BARD1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	5	239.9×	9e-11	BRCA2, BRCA1, NBN, ATM, BARD1
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	7	60.3×	1e-10	BRCA1, TP53, CHEK2, NBN, ATM, BARD1, RAD50
HDR through Single Strand Annealing (SSA)	6	103.3×	1e-10	BRCA1, BRIP1, NBN, ATM, BARD1, RAD50
Resolution of D-Loop Structures	5	186.6×	3e-10	BRCA2, BRCA1, NBN, ATM, BARD1
Diseases of DNA repair	5	167.9×	6e-10	BRCA2, BRCA1, NBN, ATM, BARD1
Homology Directed Repair	5	90.8×	1e-08	BRCA2, BRCA1, NBN, ATM, BARD1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	5	90.8×	1e-08	BRCA2, BRCA1, NBN, ATM, BARD1
Meiotic recombination	6	45.8×	2e-08	BRCA2, BRCA1, NBN, ATM, RAD50, RAD51C
Processing of DNA double-strand break ends	6	40.3×	4e-08	BRCA1, BRIP1, NBN, ATM, BARD1, RAD50
DNA Double-Strand Break Repair	5	73.0×	4e-08	BRCA2, BRCA1, NBN, ATM, BARD1
DNA Double Strand Break Response	4	112.0×	3e-07	BRCA1, NBN, ATM, BARD1
Nonhomologous End-Joining (NHEJ)	5	49.4×	3e-07	BRCA1, NBN, ATM, BARD1, RAD50
Sensing of DNA Double Strand Breaks	3	335.9×	4e-07	NBN, ATM, RAD50
G2/M Checkpoints	5	39.5×	8e-07	BRCA1, TP53, NBN, ATM, BARD1
Regulation of TP53 Activity	5	39.1×	8e-07	BRCA1, STK11, NBN, ATM, BARD1
Meiosis	4	67.2×	2e-06	BRCA2, BRCA1, 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 19 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	8	85.5×	7e-12	BRCA2, BRCA1, TP53, CHEK2, BRIP1, NBN, ATM, RAD50
homologous recombination	5	369.6×	2e-10	BRCA1, BRIP1, NBN, BARD1, RAD50
double-strand break repair via homologous recombination	7	57.5×	2e-09	BRCA2, BRCA1, PALB2, NBN, ATM, RAD50, RAD51C
DNA strand resection involved in replication fork processing	4	443.5×	8e-09	BRCA1, NBN, BARD1, RAD50
DNA damage response, signal transduction by p53 class mediator	5	94.4×	1e-07	BRCA2, TP53, CHEK2, NBN, ATM
mitotic G2/M transition checkpoint	4	168.9×	4e-07	BRCA1, NBN, BARD1, RAD50
negative regulation of telomere capping	3	532.2×	7e-07	NBN, ATM, RAD50
DNA damage response	7	19.7×	1e-06	BRCA1, STK11, TP53, CHEK2, ATM, BARD1, RAD50
cellular response to ionizing radiation	4	86.5×	5e-06	BRCA2, BRCA1, TP53, BARD1
DNA damage checkpoint signaling	4	82.5×	5e-06	CHEK2, BRIP1, NBN, ATM
regulation of cell cycle	6	23.6×	5e-06	BRCA1, STK11, TP53, NBN, ATM, BARD1
telomere maintenance via recombination	3	241.9×	6e-06	BRCA2, RAD50, RAD51C
DNA double-strand break processing	3	241.9×	6e-06	NBN, ATM, RAD50
regulation of DNA damage checkpoint	3	177.4×	2e-05	BRCA2, BRCA1, BARD1
replicative senescence	3	156.5×	2e-05	TP53, CHEK2, ATM
cellular response to gamma radiation	3	95.0×	9e-05	TP53, CHEK2, ATM
reciprocal meiotic recombination	3	88.7×	1e-04	ATM, RAD50, RAD51C
telomeric 3’ overhang formation	2	443.5×	1e-04	NBN, RAD50
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	3	78.3×	1e-04	BRCA2, TP53, CHEK2
DNA repair	5	16.8×	2e-04	BRCA1, BRIP1, BARD1, RAD50, RAD51C
mitotic G2 DNA damage checkpoint signaling	3	70.0×	2e-04	BRCA1, NBN, ATM
cellular response to indole-3-methanol	2	354.8×	2e-04	BRCA1, CDH1
response to ionizing radiation	3	64.9×	2e-04	BRCA1, STK11, ATM
nucleotide-excision repair	3	60.5×	2e-04	BRCA2, TP53, BRIP1
regulation of signal transduction by p53 class mediator	3	60.5×	2e-04	STK11, CHEK2, ATM
somitogenesis	3	59.1×	2e-04	TP53, PALB2, ATM
positive regulation of double-strand break repair	3	54.3×	3e-04	NBN, ATM, RAD50
intrinsic apoptotic signaling pathway in response to DNA damage	3	51.2×	4e-04	BRCA1, CHEK2, ATM
cellular senescence	3	46.7×	5e-04	BRCA2, TP53, ATM
telomere maintenance	3	42.2×	6e-04	NBN, ATM, RAD50

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 14

Druggability breadth: 11 of 20 evidence-associated genes (55%) 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
STK11	FEDRATINIB
TP53	NITROFURANTOIN
CHEK2	NERATINIB
ATM	AMIODARONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
ATM	35	4
CHEK2	30	4
STK11	17	4
BRCA1	12	4
RAD50	1	2
BRCA2	0	0
CD68	0	0
CDH1	0	0
BRIP1	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
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	STK11
SUNITINIB	4	CHEK2, STK11
MIDOSTAURIN	4	STK11
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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
CHEK2	690	Binding:687, Functional:2, ADMET:1
STK11	244	Binding:244
ATM	240	Binding:233, Functional:5, ADMET:2
CDH1	18	Binding:18
BRCA1	13	Binding:9, Functional:4
PTEN	8	Binding:8
RAD50	7	Binding:7
NBN	2	Binding:2
CD68	1	Binding:1
PMS2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRCA1	2.3.2.27	RING-type E3 ubiquitin transferase
STK11	2.7.11.1	non-specific serine/threonine protein kinase
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
BRIP1	3.6.4.12	DNA helicase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
BARD1	2.3.2.27	RING-type E3 ubiquitin transferase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
STK11	244
TP53	869
CHEK2	690
ATM	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 19; 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
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	STK11
SUNITINIB	4	CHEK2, STK11
MIDOSTAURIN	4	STK11
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

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	BRCA1, STK11, TP53, CHEK2, ATM
B	Phased (≥1) drug, not yet approved	1	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	12	BRCA2, CD68, CDH1, PALB2, TMEM132E, GPSM2, KLLN, RNFT1-DT, NBN, PMS2 (+2 more)

Undrugged target profiles

14 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
NBN	2	RAD50, ATM, BRCA1
PTEN	8	STK11, TP53
CD68	1	—
CDH1	18	—
TMEM132E	0	—
GPSM2	0	—
KLLN	0	—
RNFT1-DT	0	—
PMS2	1	—
BARD1	0	—
RAD51C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: BRCA2, BRCA1, STK11, TP53, CHEK2, CDH1, BRIP1, PALB2, KLLN, ATM, PMS2, BARD1, PTEN, RAD50, RAD51C, CD68, TMEM132E, GPSM2, RNFT1-DT, NBN