MLH3

Summary

MLH3 (mutL homolog 3, HGNC:7128) is a protein-coding gene on chromosome 14q24.3, encoding DNA mismatch repair protein Mlh3 (Q9UHC1). Probably involved in the repair of mismatches in DNA.

This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined.

Source: NCBI Gene 27030 — RefSeq curated summary.

At a glance

• Gene–disease (curated): colorectal cancer, hereditary nonpolyposis, type 7 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 3,350 total — 9 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 9
• MANE Select transcript: NM_001040108

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7128
Approved symbol	MLH3
Name	mutL homolog 3
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000119684
Ensembl biotype	protein_coding
OMIM	604395
Entrez	27030

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000355774, ENST00000380968, ENST00000553263, ENST00000553713, ENST00000554697, ENST00000555144, ENST00000555415, ENST00000555499, ENST00000555671, ENST00000556257, ENST00000556453, ENST00000557648, ENST00000930870, ENST00000930871, ENST00000930872, ENST00000930873, ENST00000930874, ENST00000930875, ENST00000930876, ENST00000930877, ENST00000971038

RefSeq mRNA: 2 — MANE Select: NM_001040108 NM_001040108, NM_014381

CCDS: CCDS32123, CCDS9837

Canonical transcript exons

ENST00000355774 — 13 exons

Exon	Start	End
ENSE00001097899	75046376	75049718
ENSE00001097903	75038340	75038412
ENSE00001152173	75018829	75018980
ENSE00001362855	75013775	75017201
ENSE00003488554	75039911	75040015
ENSE00003581887	75030543	75030702
ENSE00003584609	75033419	75033490
ENSE00003592755	75022814	75022892
ENSE00003595942	75042379	75042477
ENSE00003628932	75041615	75041700
ENSE00003633165	75022995	75023018
ENSE00003650910	75032068	75032179
ENSE00003902301	75051380	75051467

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 95.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.1593 / max 186.5970, expressed in 1680 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144096	8.1593	1680

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.12	gold quality
mononuclear cell	CL:0000842	94.79	gold quality
leukocyte	CL:0000738	94.29	gold quality
ventricular zone	UBERON:0003053	91.30	gold quality
calcaneal tendon	UBERON:0003701	90.69	gold quality
colonic epithelium	UBERON:0000397	89.93	gold quality
right lobe of thyroid gland	UBERON:0001119	89.10	gold quality
adrenal tissue	UBERON:0018303	89.09	gold quality
left lobe of thyroid gland	UBERON:0001120	88.67	gold quality
granulocyte	CL:0000094	88.65	gold quality
right adrenal gland cortex	UBERON:0035827	88.29	gold quality
thyroid gland	UBERON:0002046	88.12	gold quality
right adrenal gland	UBERON:0001233	87.96	gold quality
tibial nerve	UBERON:0001323	87.76	gold quality
mucosa of stomach	UBERON:0001199	87.64	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.57	gold quality
ganglionic eminence	UBERON:0004023	87.45	gold quality
left adrenal gland cortex	UBERON:0035825	87.22	gold quality
left adrenal gland	UBERON:0001234	87.17	gold quality
metanephros cortex	UBERON:0010533	87.12	gold quality
lower esophagus mucosa	UBERON:0035834	87.03	gold quality
cortical plate	UBERON:0005343	87.01	gold quality
adrenal gland	UBERON:0002369	86.89	gold quality
adrenal cortex	UBERON:0001235	86.63	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.56	gold quality
lower esophagus	UBERON:0013473	86.55	gold quality
adenohypophysis	UBERON:0002196	86.46	gold quality
apex of heart	UBERON:0002098	86.40	gold quality
endocervix	UBERON:0000458	86.37	gold quality
right lobe of liver	UBERON:0001114	86.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN, TP53, TP73

miRNA regulators (miRDB)

125 targeting MLH3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 28)

• Little evidence for involvement of MLH3 in colorectal cancer predisposition. (PMID:12800209)
• at pachynema, when chromosomes are fully paired, we find significant heterogeneity in the localization of the MutL homologs, MLH1 and MLH3, among human oocyte populations (PMID:15558497)
• The identification of inherited missense variants, somatic missense mutations (present in 3 of 57 tumors), and LOH in the tumor from a patient with a germ line missense change suggest a role for MLH3 in endometrial tumorigenesis. (PMID:16885347)
• Mutations of Mlh3 may work together with other genes in an accumulated manner and result in an increased risk of esophageal tumor (PMID:16981255)
• in absence of hPMS2, hMLH3 (hMutLgamma) is located in the nucleus, suggesting a conditional activity in MMR and supporting its role as a low-risk gene in hereditary non-polyposis colorectal cancer (PMID:17203173)
• Two simultaneous hMLH3 variants might predispose to spermatogenic arrest. (PMID:17482610)
• results suggest that the endonuclease activity of MutLalpha is important not only in MMR-dependent mutation avoidance but also for recombination and damage response functions (PMID:17567544)
• MLH3 and EXO1 alterations in familial colorectal cancer patients not fulfilling Amsterdam criteria. (PMID:17656264)
• To assess the significance of the inherited sequence variations in MLH3, we functionally characterized seven missense mutations (PMID:18521850)
• Mlh3 nullizygosity significantly increased Apc frameshift mutations and tumor multiplicity. (PMID:18551179)
• the different biochemical assays yielded no evidence that the eight MLH3 unclassified variants (missense mutations) tested are the cause of hereditary colorectal cancer, including Lynch syndrome (PMID:19156873)
• hMLH3 mRNA is present at low levels in numerous tissues but high levels in testis. hMLH3 functions in meiosis as well as hMSH2-hMSH3 repair processes & has little if any role in Hereditary Non-Polyposis Colorectal Cancer (HNPCC). (PMID:19483466)
• There is an association of polymorphism C85T in MSH5 or C2531T in MLH3 with male infertility, specifically azoospermia or severe oligozoospermia, and interaction between these MSH5 and MLH3 polymorphisms increased the risk of developing male infertility (PMID:19808033)
• the MutSbeta-MutLalpha interaction is mediated in part by residues ((L/I)SRFF) embedded within the MSH3 PCNA-binding motif (PMID:20154325)
• The experiments show recruitment and persistence of MutLgamma-heterodimers at UVA-induced DNA lesions. (PMID:23696135)
• Results indicate that CT(844)-CC(942) was associated with a high risk of cervical carcinoma and cervical intraepithelial neoplasia, and the CC(844)-CT(942) decreased the risk. (PMID:24759751)
• MutL homolog 3 (MLH3) promoter methylation was observed in 61% of oligoastrocytoma and 27% of astrocytoma. (PMID:26303387)
• A polymorphism within the MLH3 gene is associated with oligozoospermia in Caucasian men of a certain area. (PMID:26520453)
• MLH3 germline variants are associated with colon cancer patients belonging to families with Lynch syndrome-associated brain tumors. (PMID:27401157)
• MLH3 isoform 1 is active in GAA*TTC repeat expansion while the nuclease-deficient MLH3 isoform 2 is not. (PMID:29529236)
• The effects of chronic smoking on oral mucosa led to the methylation of genes MRE11A PMS2, XRCC1 and MLH3, but resulted in a reduction of gene expression of MRE11A and PMS2, which showed >/=50% methylation. These results provide evidence that smoking cause methylation and reduced expression of repair genes. (PMID:29775861)
• Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer. (PMID:30573798)
• rs175080 in MLH3 was not significantly different between idiopathic male infertility and control (p > 0.05). (PMID:31342644)
• MutLgamma, the MLH1-MLH3 heterodimer, is a unique endonuclease that can initiate triplet repeat DNA expansions. (PMID:32015124)
• Regulation of the MLH1-MLH3 endonuclease in meiosis. (PMID:32814904)
• Genetic evidence for the involvement of mismatch repair proteins, PMS2 and MLH3, in a late step of homologous recombination. (PMID:33453991)
• A loss-of-function variant in DNA mismatch repair gene MLH3 underlies severe oligozoospermia. (PMID:33517345)
• Exonic sequencing and MLH3 gene expression analysis of breast cancer patients. (PMID:34933735)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mlh3	ENSDARG00000056334
mus_musculus	Mlh3	ENSMUSG00000021245
rattus_norvegicus	Mlh3	ENSRNOG00000006699

Paralogs (3): PMS1 (ENSG00000064933), MLH1 (ENSG00000076242), PMS2 (ENSG00000122512)

Protein

Protein identifiers

DNA mismatch repair protein Mlh3 — Q9UHC1 (reviewed: Q9UHC1)

Alternative names: MutL protein homolog 3

All UniProt accessions (8): Q9UHC1, G3V384, G3V3E0, G3V419, H0YJ15, H0YJA3, H0YJB4, H0YJU3

UniProt curated annotations — full annotation on UniProt →

Function. Probably involved in the repair of mismatches in DNA.

Subunit / interactions. Heterodimer of MLH1 and MLH3. Interacts with MTMR15/FAN1.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Disease relevance. Hereditary non-polyposis colorectal cancer 7 (HNPCC7) [MIM:614385] An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term ‘suspected HNPCC’ or ‘incomplete HNPCC’ can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. The disease is caused by variants affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DNA mismatch repair MutL/HexB family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UHC1-1	1	yes
Q9UHC1-2	2

RefSeq proteins (2): NP_001035197, NP_055196 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002099	MutL/Mlh/PMS	Family
IPR013507	DNA_mismatch_S5_2-like	Domain
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR014762	DNA_mismatch_repair_CS	Conserved_site
IPR014790	MutL_C	Domain
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR036890	HATPase_C_sf	Homologous_superfamily
IPR037198	MutL_C_sf	Homologous_superfamily
IPR038973	MutL/Mlh/Pms-like	Family
IPR042120	MutL_C_dimsub	Homologous_superfamily
IPR042121	MutL_C_regsub	Homologous_superfamily

Pfam: PF01119, PF08676, PF13589

UniProt features (36 total): sequence variant 30, region of interest 2, compositionally biased region 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHC1-F1	56.14	0.22

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-912446	Meiotic recombination
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle

MSigDB gene sets: 0 (showing top):

GO Biological Process (8): mismatch repair (GO:0006298), synaptonemal complex assembly (GO:0007130), reciprocal meiotic recombination (GO:0007131), male meiotic nuclear division (GO:0007140), female meiosis I (GO:0007144), intracellular protein localization (GO:0008104), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (8): chromatin binding (GO:0003682), satellite DNA binding (GO:0003696), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), centromeric DNA binding (GO:0019237), mismatched DNA binding (GO:0030983), ATP-dependent DNA damage sensor activity (GO:0140664), protein binding (GO:0005515)

GO Cellular Component (8): synaptonemal complex (GO:0000795), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nucleoplasm (GO:0005654), chiasma (GO:0005712), mismatch repair complex (GO:0032300), condensed chromosome (GO:0000793), condensed nuclear chromosome (GO:0000794)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Meiosis	1
Reproduction	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
meiosis I	2
meiotic cell cycle	2
binding	2
sequence-specific double-stranded DNA binding	2
cellular anatomical structure	2
DNA repair	1
homologous chromosome pairing at meiosis	1
cellular component assembly	1
chromosome organization involved in meiotic cell cycle	1
synaptonemal complex organization	1
reciprocal homologous recombination	1
meiotic cell cycle process	1
male gamete generation	1
meiotic nuclear division	1
female meiotic nuclear division	1
female gamete generation	1
macromolecule localization	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
double-stranded DNA binding	1
ATP-dependent activity, acting on DNA	1
DNA damage sensor activity	1
synaptonemal structure	1
germ cell nucleus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
condensed nuclear chromosome	1
intracellular anatomical structure	1
protein-containing complex	1
chromosome	1
nuclear chromosome	1
condensed chromosome	1
nucleus	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

52 interactions, top by confidence:

A	B	Type	Score
MLH1	PMS2	psi-mi:“MI:0915”(physical association)	0.970
MLH1	PMS1	psi-mi:“MI:0914”(association)	0.830
MLH1	MLH3	psi-mi:“MI:0915”(physical association)	0.780
MLH3	MLH1	psi-mi:“MI:0915”(physical association)	0.780
MLH3	BPNT2	psi-mi:“MI:0915”(physical association)	0.400
MLH3	AKT1	psi-mi:“MI:0915”(physical association)	0.370
MLH3	ALDOB	psi-mi:“MI:0915”(physical association)	0.370
ANP32B	MLH3	psi-mi:“MI:0915”(physical association)	0.370
BAAT	MLH3	psi-mi:“MI:0915”(physical association)	0.370
AOPEP	MLH3	psi-mi:“MI:0915”(physical association)	0.370
MSANTD3	MLH3	psi-mi:“MI:0915”(physical association)	0.370
MLH3	TSTD2	psi-mi:“MI:0915”(physical association)	0.370
MLH3	CDC14B	psi-mi:“MI:0915”(physical association)	0.370
CDK8	MLH3	psi-mi:“MI:0915”(physical association)	0.370
CTSV	MLH3	psi-mi:“MI:0915”(physical association)	0.370
MLH3	CYLC2	psi-mi:“MI:0915”(physical association)	0.370
MLH3	DVL1	psi-mi:“MI:0915”(physical association)	0.370
MLH3	FANCC	psi-mi:“MI:0915”(physical association)	0.370
FBP1	MLH3	psi-mi:“MI:0915”(physical association)	0.370
MLH3	FBP2	psi-mi:“MI:0915”(physical association)	0.370
MLH3	FRAT2	psi-mi:“MI:0915”(physical association)	0.370
MLH3	GALNT12	psi-mi:“MI:0915”(physical association)	0.370
MLH3	HEMGN	psi-mi:“MI:0915”(physical association)	0.370
MLH3	HRAS	psi-mi:“MI:0915”(physical association)	0.370
MLH3	HSD17B3	psi-mi:“MI:0915”(physical association)	0.370
MLH3	IGFBP3	psi-mi:“MI:0915”(physical association)	0.370
CCDC180	MLH3	psi-mi:“MI:0915”(physical association)	0.370
MLH3	LEF1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (70): MLH3 (Affinity Capture-RNA), MLH3 (Two-hybrid), MLH3 (Two-hybrid), MLH1 (Two-hybrid), MLH3 (Proximity Label-MS), AKT1 (Two-hybrid), ALDOB (Two-hybrid), ANP32B (Two-hybrid), BAAT (Two-hybrid), C9orf3 (Two-hybrid), MSANTD3 (Two-hybrid), TSTD2 (Two-hybrid), CDC14B (Two-hybrid), CDK8 (Two-hybrid), CTSV (Two-hybrid)

ESM2 similar proteins: A0JM80, A0JNH9, A6QNQ6, A7MBJ2, A8MT70, B1WC58, D3ZF42, F6SNN2, O70608, P46100, P56273, P56716, P62288, P62296, Q0P5X5, Q17RS7, Q28FY7, Q32MH5, Q56NI9, Q5QJC4, Q5RD97, Q5T5J6, Q5VYS8, Q5W0B1, Q5ZI58, Q6GNV6, Q6GPJ8, Q6P4F7, Q6P7W0, Q6PJP8, Q6ZV73, Q7YQM3, Q7YQM4, Q7ZYI3, Q7ZZH7, Q80WQ8, Q80YR6, Q8BUH8, Q8IW19, Q8L7S0

Diamond homologs: A0LJK2, A1BCW2, A1KUP6, A2RP08, A7HNR3, A8YTI0, A9M0G1, B0JS91, B0SB85, B0ST13, B1N024, B1X109, B2I9E6, B2IYW1, B3PDC3, B3QL59, B3QW86, B4RLX4, B4UCW3, B5YIZ6, B7JY11, B8J9F5, B9K7B8, O67518, P70754, Q02VS5, Q048Y5, Q04QW2, Q04Z69, Q131I8, Q1G939, Q2IIL0, Q3MEV6, Q5F8M6, Q5FLX4, Q67NL0, Q72PF7, Q7W0A6, Q7W4N5, Q7WG61

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TCF dependent signaling in response to WNT	5	16.4×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
MAPK cascade	5	16.3×	2e-03
canonical Wnt signaling pathway	5	16.3×	2e-03
osteoblast differentiation	5	12.9×	5e-03
positive regulation of cell migration	6	7.9×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

3350 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	10
Uncertain significance	2181
Likely benign	928
Benign	38

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
3779871	NM_001040108.2(MLH3):c.1619del (p.Asn540fs)	Pathogenic
4812995	NM_001040108.2(MLH3):c.3632del (p.Asn1211fs)	Pathogenic
4812997	NM_001040108.2(MLH3):c.2983del (p.Gln994_Ile995insTer)	Pathogenic
4812998	NM_001040108.2(MLH3):c.1701del (p.Phe567fs)	Pathogenic
4813006	NM_001040108.2(MLH3):c.746del (p.Met249fs)	Pathogenic
4813012	NM_001040108.2(MLH3):c.1566del (p.Gln523fs)	Pathogenic
4813022	NM_001040108.2(MLH3):c.1282dup (p.Ser428fs)	Pathogenic
4813027	NM_001040108.2(MLH3):c.673G>T (p.Glu225Ter)	Pathogenic
998145	NM_001040108.2(MLH3):c.2788del (p.Thr930fs)	Pathogenic
1802862	NM_001040108.2(MLH3):c.983_986del (p.Ile328fs)	Likely pathogenic
1802864	NM_001040108.2(MLH3):c.124del (p.Ala42fs)	Likely pathogenic
208641	NM_001040108.2(MLH3):c.2116del (p.Thr706fs)	Likely pathogenic
2576490	NM_001040108.2(MLH3):c.3450del (p.Phe1150fs)	Likely pathogenic
2664913	NM_001040108.2(MLH3):c.2799del (p.Val934fs)	Likely pathogenic
3065377	NM_001040108.2(MLH3):c.1270_1271del (p.Ser424fs)	Likely pathogenic
3765292	NM_001040108.2(MLH3):c.1729dup (p.Ala577fs)	Likely pathogenic
3765551	NM_001040108.2(MLH3):c.3956del (p.Gly1319fs)	Likely pathogenic
4278412	NM_001040108.2(MLH3):c.859dup (p.Ser287fs)	Likely pathogenic
625564	GRCh37/hg19 14q24.3(chr14:74040231-76368547)	Likely pathogenic

SpliceAI

2193 predictions. Top by Δscore:

Variant	Effect	Δscore
14:75030538:CTTA:C	donor_loss	1.0000
14:75030539:TTACC:T	donor_loss	1.0000
14:75030540:TA:T	donor_loss	1.0000
14:75030541:A:AG	donor_loss	1.0000
14:75030542:C:CT	donor_loss	1.0000
14:75032179:TCTAT:T	acceptor_loss	1.0000
14:75032180:C:CC	acceptor_gain	1.0000
14:75032180:C:T	acceptor_loss	1.0000
14:75032181:T:A	acceptor_loss	1.0000
14:75033413:CCTTA:C	donor_loss	1.0000
14:75033414:CTTA:C	donor_loss	1.0000
14:75033415:TTA:T	donor_loss	1.0000
14:75033416:TA:T	donor_loss	1.0000
14:75033417:A:AC	donor_gain	1.0000
14:75033417:A:AG	donor_loss	1.0000
14:75033418:C:CC	donor_gain	1.0000
14:75033418:C:T	donor_loss	1.0000
14:75022989:GCTTA:G	donor_loss	0.9900
14:75022990:CTTA:C	donor_loss	0.9900
14:75022991:TTACC:T	donor_loss	0.9900
14:75022992:TAC:T	donor_loss	0.9900
14:75022994:C:CG	donor_loss	0.9900
14:75023016:TTCCT:T	acceptor_loss	0.9900
14:75023017:TCC:T	acceptor_loss	0.9900
14:75023018:CCTGC:C	acceptor_loss	0.9900
14:75023020:T:G	acceptor_loss	0.9900
14:75030541:A:AC	donor_gain	0.9900
14:75030541:ACCT:A	donor_gain	0.9900
14:75030542:C:CC	donor_gain	0.9900
14:75030542:CCT:C	donor_gain	0.9900

AlphaMissense

9683 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:75033466:T:A	D1223V	0.998
14:75038386:A:C	F1199L	0.998
14:75038386:A:T	F1199L	0.998
14:75038387:A:G	F1199S	0.998
14:75038388:A:G	F1199L	0.998
14:75018967:A:C	F1368L	0.997
14:75018967:A:T	F1368L	0.997
14:75018969:A:G	F1368L	0.997
14:75033445:C:G	R1230P	0.997
14:75033448:T:A	E1229V	0.997
14:75038381:G:T	A1201D	0.997
14:75049557:A:C	S33R	0.997
14:75049557:A:T	S33R	0.997
14:75049559:T:G	S33R	0.997
14:75033436:A:G	L1233P	0.996
14:75033466:T:G	D1223A	0.996
14:75033447:C:A	E1229D	0.995
14:75033447:C:G	E1229D	0.995
14:75033472:A:G	L1221P	0.995
14:75039939:A:G	F1181S	0.995
14:75018880:T:A	R1397S	0.994
14:75018880:T:G	R1397S	0.994
14:75018894:A:G	C1393R	0.994
14:75018932:A:G	L1380P	0.994
14:75022820:A:G	C1362R	0.994
14:75018881:C:G	R1397T	0.993
14:75018968:A:G	F1368S	0.993
14:75033439:C:G	R1232P	0.993
14:75033446:G:T	R1230S	0.993
14:75033465:A:C	D1223E	0.993

dbSNP variants (sampled 300 via entrez): RS1000037699 (14:75018181 G>GCAA), RS1000068759 (14:75030086 C>T), RS1000221064 (14:75037581 T>C), RS1000299905 (14:75051115 A>G), RS1000413129 (14:75044021 G>A), RS1000503950 (14:75030491 A>G), RS1000561664 (14:75037701 C>T), RS1000595125 (14:75044212 C>A), RS1000620769 (14:75036574 C>G,T), RS1000747308 (14:75031145 TA>T), RS1000921253 (14:75045784 C>T), RS1001137948 (14:75045400 T>C), RS1001203377 (14:75046045 T>C), RS1001221987 (14:75038789 G>T), RS1001305990 (14:75052196 G>A)

Disease associations

OMIM: gene MIM:604395 | disease phenotypes: MIM:614385, MIM:167000, MIM:114500, MIM:114480, MIM:120435, MIM:608089

GenCC curated gene-disease

Disease	Classification	Inheritance
colorectal cancer, hereditary nonpolyposis, type 7	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
colorectal cancer, hereditary nonpolyposis, type 7	Limited	AD
intestinal polyposis syndrome	Limited	AR

Mondo (13): endometrial carcinoma (MONDO:0002447), colorectal cancer, hereditary nonpolyposis, type 7 (MONDO:0013725), ovarian cancer (MONDO:0008170), colorectal cancer (MONDO:0005575), hereditary neoplastic syndrome (MONDO:0015356), Lynch syndrome (MONDO:0005835), hereditary breast carcinoma (MONDO:0016419), breast carcinoma (MONDO:0004989), breast cancer (MONDO:0007254), Lynch syndrome 1 (MONDO:0007356), colon carcinoma (MONDO:0002032), endometrial cancer (MONDO:0011962), primary ovarian failure (MONDO:0005387)

Orphanet (6): Lynch syndrome (Orphanet:144), Rare ovarian cancer (Orphanet:213500), Inherited cancer-predisposing syndrome (Orphanet:140162), Hereditary breast cancer (Orphanet:227535), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

9 total (10 of 9 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001442	Typified by somatic mosaicism
HP:0002891	Uterine leiomyosarcoma
HP:0003003	Colon cancer
HP:0005584	Renal cell carcinoma
HP:0006716	Hereditary nonpolyposis colorectal carcinoma
HP:0006740	Transitional cell carcinoma of the bladder
HP:0006753	Neoplasm of the stomach
HP:0012114	Endometrial carcinoma
HP:0003002	Breast carcinoma

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001725_26	Inflammatory bowel disease	3.000000e-08
GCST005237_3	Mood instability	1.000000e-06
GCST005238_3	Mood instability	3.000000e-09
GCST010002_156	Refractive error	7.000000e-25

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008475	mood instability measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C562840	Breast Cancer, Familial (supp.)
C565777	Colorectal Cancer, Hereditary Nonpolyposis, Type 7 (supp.)
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	7
sodium arsenite	decreases expression, increases expression	2
Estradiol	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
myristicin	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
CGP 52608	affects binding, increases reaction	1
riccardin D	increases expression	1
Decitabine	increases expression	1
Leflunomide	decreases expression	1
Glyphosate	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Methyl Methanesulfonate	decreases expression	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	affects response to substance	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00719017	PHASE4	UNKNOWN	Upper Vaginectomy Versus Brachytherapy in Patients With Early Stage Endometrial Cancer Treated With Laparoscopic Surgery
NCT02543710	PHASE4	RECRUITING	Biomarker Guided Treatment in Gynaecological Cancer
NCT03349463	PHASE4	UNKNOWN	Evaluation of Fluciclovine Uptake in Patients With Cervical, Ovarian Epithelial or Endometrial Cancers.
NCT03752606	PHASE4	COMPLETED	Application of Tachosil During Lymphadenectomy
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT06049693	PHASE4	COMPLETED	Iron Prehabilitation in Endometrial Cancer
NCT06726291	PHASE4	RECRUITING	Akynzeo as Antiemetic Treatment in Patients With Endometrial Cancer
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT07281547	PHASE4	NOT_YET_RECRUITING	Low Dose Aspirin to Lower Inflammation and Prevent Endometrial Cancer in Postmenopausal Women With Non-atrophic Endometrial Changes and Pain
NCT07462663	PHASE4	NOT_YET_RECRUITING	SHAPE-ENDO: Multimodal Pre-Surgical Optimization in Patients With Obesity and Early-Stage Endometrial Cancer (Phase 1)
NCT00002459	PHASE3	COMPLETED	Radiation Therapy or No Further Treatment Following Surgery in Treating Patients With Cancer of the Uterus
NCT00002493	PHASE3	COMPLETED	Radiation Therapy Compared With Combination Chemotherapy in Treating Patients With Advanced Endometrial Cancer
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002920	PHASE3	COMPLETED	S9630, Medroxyprogesterone in Treating Women With Breast Cancer
NCT00002976	PHASE3	TERMINATED	Estrogen Replacement Therapy in Treating Women With Early-Stage Endometrial Cancer
NCT00003267	PHASE3	COMPLETED	Pelvic Drains After Radical Hysterectomy in Treating Patients With Uterine, Cervical, or Vaginal Cancer
NCT00003691	PHASE3	COMPLETED	Combination Chemotherapy With or Without G-CSF in Treating Patients With Stage III, Stage IV, or Recurrent Endometrial Cancer
NCT00003749	PHASE3	COMPLETED	Surgery With or Without Lymphadenectomy and Radiation Therapy in Treating Patients With Endometrial Cancer
NCT00005583	PHASE3	COMPLETED	Radiation Therapy With or Without Chemotherapy in Treating Patients With High-Risk Endometrial Cancer
NCT00006027	PHASE3	COMPLETED	Comparison of Radiation Therapy With or Without Combination Chemotherapy Following Surgery in Treating Patients With Stage I or Stage II Endometrial Cancer
NCT00016341	PHASE3	TERMINATED	Combination Chemotherapy Compared With Hormone Therapy in Treating Patients With Recurrent, Stage III, or Stage IV Endometrial Cancer
NCT00033605	PHASE3	COMPLETED	Octreotide in Preventing Diarrhea in Patients Who Are Undergoing Radiation Therapy to the Pelvis
NCT00096408	PHASE3	COMPLETED	Laparoscopic Approach to Cancer of the Endometrium
NCT00245050	PHASE3	COMPLETED	Pyridoxine in Preventing Hand-Foot Syndrome in Patients Who Are Receiving Liposomal Doxorubicin for Cancer
NCT00376844	PHASE3	COMPLETED	External-Beam Radiation Therapy Compared With Vaginal Brachytherapy After Surgery for Stage I Endometrial Cancer
NCT00411138	PHASE3	UNKNOWN	Randomized Trial of Radiation Therapy With or Without Chemotherapy for Endometrial Cancer
NCT00566644	PHASE3	TERMINATED	Intrauterine Levonorgestrel and Observation or Observation Alone in Preventing Atypical Endometrial Hyperplasia and Endometrial Cancer in Women With Hereditary Non-Polyposis Colorectal Cancer or Lynch Syndrome
NCT00883116	PHASE3	TERMINATED	A Study of Ixabepilone as Second-line Therapy for Locally Advanced, Recurrent, or Metastatic Endometrial Cancer
NCT01087268	PHASE3	UNKNOWN	Hyperbaric Oxygen Therapy in Treating Long-Term Gastrointestinal Adverse Effects Caused by Radiation Therapy in Patients With Pelvic Cancer
NCT01470677	PHASE3	COMPLETED	Tachosil for the Prevention of Symptomatic Lymph Cysts
NCT01672892	PHASE3	COMPLETED	Standard Versus Intensity-Modulated Pelvic Radiation Therapy in Treating Patients With Endometrial or Cervical Cancer
NCT01767155	PHASE3	COMPLETED	Zoptarelin Doxorubicin (AEZS 108) as Second Line Therapy for Endometrial Cancer
NCT02584478	PHASE3	UNKNOWN	Phase 1/2a/3 Evaluation of Adding AL3818 to Standard Platinum-Based Chemotherapy in Subjects With Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma (AL3818-US-002)
NCT02762214	PHASE3	UNKNOWN	Role of Uterine Manipulator in Hysterectomy - Ro.Man.HY
NCT03469674	PHASE3	ACTIVE_NOT_RECRUITING	PORTEC-4a: Molecular Profile-based Versus Standard Adjuvant Radiotherapy in Endometrial Cancer
NCT03555422	PHASE3	COMPLETED	Maintenance With Selinexor/Placebo After Combination Chemotherapy in Participants With Endometrial Cancer [SIENDO]
NCT03603184	PHASE3	COMPLETED	Atezolizumab Trial in Endometrial Cancer - AtTEnd
NCT03785288	PHASE3	RECRUITING	Vaginal Cuff Brachytherapy Fractionation Study