MLH3

mutL homolog 3, the group of MutL homologs

Basic information

Region (hg38): 14:75013768-75051532

Links

ENSG00000119684 ∙ NCBI:27030 ∙ OMIM:604395 ∙ HGNC:7128 ∙ Uniprot:Q9UHC1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• colorectal cancer, hereditary nonpolyposis, type 7 (Moderate), mode of inheritance: AD
• colorectal cancer, hereditary nonpolyposis, type 7 (Limited), mode of inheritance: AR
• colorectal cancer, hereditary nonpolyposis, type 7 (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Colorectal cancer, hereditary nonpolyposis type 7; Endometrial carcinoma	AD	Oncologic	Surveillance to allow early detection and treatment of tumors (associated with colorectal cancer) may be beneficial to reduce morbidity and mortality	Oncologic	12702580; 16885347
The clinical significance of mutations in this gene is unclear

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MLH3 gene.

• Hereditary cancer-predisposing syndrome (1744 variants)
• Colorectal cancer, hereditary nonpolyposis, type 7 (971 variants)
• not specified (162 variants)
• not provided (66 variants)
• MLH3-related condition (25 variants)
• Ovarian cancer (10 variants)
• Lynch syndrome (10 variants)
• Endometrial carcinoma (7 variants)
• Inborn genetic diseases (6 variants)
• Colorectal cancer, non-polyposis (3 variants)
• Vanishing white matter disease (3 variants)
• Endometrial carcinoma;Colorectal cancer;Colorectal cancer, hereditary nonpolyposis, type 7 (2 variants)
• Colorectal cancer, hereditary nonpolyposis, type 7;Colorectal cancer;Endometrial carcinoma (2 variants)
• Carcinoma of colon (1 variants)
• Endometrial cancer (1 variants)
• Hereditary cancer (1 variants)
• Premature ovarian failure (1 variants)
• Colorectal cancer (1 variants)
• Lynch syndrome 1 (1 variants)
• Colorectal cancer;Colorectal cancer, hereditary nonpolyposis, type 7;Endometrial carcinoma (1 variants)
• Breast carcinoma (1 variants)
• Endometrial carcinoma;Colorectal cancer, hereditary nonpolyposis, type 7;Colorectal cancer (1 variants)
• Colorectal cancer, hereditary nonpolyposis, type 7;Endometrial carcinoma (1 variants)
• Malignant tumor of breast (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MLH3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	535	2	539
missense			1239	57	4	1300
nonsense			31			31
start loss			2			2
frameshift		5	60			65
inframe indel			15			15
splice donor/acceptor (+/-2bp)			7		1	8
splice region			12	16		28
non coding			53	76	31	160
Total	0	5	1409	668	38

Variants in MLH3

This is a list of pathogenic ClinVar variants found in the MLH3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-75013824-A-G		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 12, 2018)
14-75013876-G-A		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 13, 2018)
14-75013934-T-C		Lynch syndrome • Vanishing white matter disease • Colorectal cancer, hereditary nonpolyposis, type 7	Benign/Likely benign (Feb 18, 2020)
14-75013942-G-A		Vanishing white matter disease • Lynch syndrome • Colorectal cancer, hereditary nonpolyposis, type 7	Likely benign (Jan 13, 2018)
14-75013942-G-C		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 12, 2018)
14-75013977-G-C		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 13, 2018)
14-75013988-G-A		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 12, 2018)
14-75014033-TG-T		Lynch syndrome	Uncertain significance (Jun 14, 2016)
14-75014035-C-A		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 13, 2018)
14-75014117-G-A		Vanishing white matter disease • Lynch syndrome • Colorectal cancer, hereditary nonpolyposis, type 7	Benign/Likely benign (Jan 13, 2018)
14-75014403-T-C		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 13, 2018)
14-75014492-A-G		Colorectal cancer, hereditary nonpolyposis, type 7	Likely benign (Jan 13, 2018)
14-75014587-G-A		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 15, 2018)
14-75014612-G-A		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 13, 2018)
14-75014613-T-C		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 13, 2018)
14-75014665-C-T		Colorectal cancer, hereditary nonpolyposis, type 7	Benign (Jan 13, 2018)
14-75014675-A-G		Colorectal cancer, hereditary nonpolyposis, type 7	Likely benign (Jan 13, 2018)
14-75014684-G-T		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 13, 2018)
14-75014908-G-A		Colorectal cancer, hereditary nonpolyposis, type 7	Likely benign (Jan 13, 2018)
14-75014996-G-A		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 12, 2018)
14-75015024-C-A		Colorectal cancer, hereditary nonpolyposis, type 7	Conflicting classifications of pathogenicity (Sep 01, 2022)
14-75015092-A-T		Colorectal cancer, hereditary nonpolyposis, type 7	Uncertain significance (Jan 13, 2018)
14-75015186-T-C		Colorectal cancer, hereditary nonpolyposis, type 7	Likely benign (Jan 12, 2018)
14-75015205-A-G		Colorectal cancer, hereditary nonpolyposis, type 7	Benign (Jan 12, 2018)
14-75015315-C-T		Colorectal cancer, hereditary nonpolyposis, type 7	Likely benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MLH3	protein_coding	protein_coding	ENST00000355774	12	37769

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.90e-8	1.00	125301	3	444	125748	0.00178

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.736	687	743	0.924	0.0000388	9650
Missense in Polyphen		171	184.03	0.92919		2321
Synonymous	1.48	240	271	0.885	0.0000145	2705
Loss of Function	4.00	22	53.6	0.411	0.00000263	750

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0197	0.0197
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000272	0.000272
Finnish	0.00258	0.00250
European (Non-Finnish)	0.000246	0.000246
Middle Eastern	0.000272	0.000272
South Asian	0.000555	0.000555
Other	0.000651	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Probably involved in the repair of mismatches in DNA.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:11317354}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mismatch repair - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.153

Intolerance Scores

• loftool: 0.147
• rvis_EVS: 1.86
• rvis_percentile_EVS: 97.16

Haploinsufficiency Scores

• pHI: 0.186
• hipred: Y
• hipred_score: 0.519
• ghis: 0.472

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.572

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Mlh3
• Phenotype: endocrine/exocrine gland phenotype; reproductive system phenotype

Gene ontology

• Biological process: mismatch repair;synaptonemal complex assembly;reciprocal meiotic recombination;male meiotic nuclear division;female meiosis I;protein localization
• Cellular component: synaptonemal complex;male germ cell nucleus;nucleus;chiasma;mismatch repair complex;MutLalpha complex
• Molecular function: chromatin binding;satellite DNA binding;protein binding;ATP binding;ATPase activity;centromeric DNA binding;mismatched DNA binding