Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000249.4(MLH1):c.923A>C (p.His308Pro)

CA352048631

561172 (ClinVar)

Gene: MLH1 (HGNC:4292)

Condition: colorectal cancer, hereditary nonpolyposis, type 2 (MONDO:0012249)

Inheritance Mode: Autosomal dominant inheritance

UUID: 016608ab-5f1d-4155-9b1b-a832115b425a

Approved on: 2024-10-11

Published on: 2024-10-11

HGVS expressions

NM_000249.4(MLH1):c.923A>C (p.His308Pro)

NM_000249.4:c.923A>C

NC_000003.12:g.37020348A>C

CM000665.2:g.37020348A>C

NC_000003.11:g.37061839A>C

CM000665.1:g.37061839A>C

NC_000003.10:g.37036843A>C

NG_007109.2:g.31999A>C

ENST00000413740.2:c.923A>C

ENST00000429117.6:c.629A>C

ENST00000450420.6:c.923A>C

ENST00000456676.7:c.923A>C

ENST00000458009.6:c.884+2749A>C

ENST00000492474.6:c.200A>C

ENST00000616768.6:c.923A>C

ENST00000673673.2:c.923A>C

ENST00000231790.8:c.923A>C

ENST00000413212.2:c.68-5289A>C

ENST00000432299.6:c.*871-5289A>C

ENST00000441265.6:c.200A>C

ENST00000442249.6:n.731A>C

ENST00000447829.6:c.*34A>C

ENST00000539477.6:c.200A>C

ENST00000673673.1:c.876A>C

ENST00000673713.1:n.954A>C

ENST00000673715.1:c.923A>C

ENST00000673889.1:n.305A>C

ENST00000673897.1:c.*715A>C

ENST00000673899.1:c.677+8249A>C

ENST00000673947.1:c.*1063A>C

ENST00000673972.1:c.*801A>C

ENST00000673990.1:n.814A>C

ENST00000674019.1:c.200A>C

ENST00000674107.1:n.771A>C

ENST00000674111.1:c.923A>C

ENST00000231790.6:c.923A>C

ENST00000413212.1:c.114-5289A>C

ENST00000435176.5:c.629A>C

ENST00000441265.5:c.200A>C

ENST00000447829.5:c.210A>C

ENST00000455445.6:c.200A>C

ENST00000456676.6:c.898A>C

ENST00000458009.5:c.225+2749A>C

ENST00000458205.6:c.200A>C

ENST00000536378.5:c.200A>C

ENST00000539477.5:c.200A>C

NM_000249.3:c.923A>C

NM_001167617.1:c.629A>C

NM_001167618.1:c.200A>C

NM_001167619.1:c.200A>C

NM_001258271.1:c.923A>C

NM_001258273.1:c.200A>C

NM_001258274.1:c.200A>C

NM_001167617.2:c.629A>C

NM_001167618.2:c.200A>C

NM_001167619.2:c.200A>C

NM_001258274.2:c.200A>C

NM_001354615.1:c.200A>C

NM_001354616.1:c.200A>C

NM_001354617.1:c.200A>C

NM_001354618.1:c.200A>C

NM_001354619.1:c.200A>C

NM_001354620.1:c.629A>C

NM_001354621.1:c.-101A>C

NM_001354622.1:c.-101A>C

NM_001354623.1:c.-101A>C

NM_001354624.1:c.-36-5289A>C

NM_001354625.1:c.-36-5289A>C

NM_001354626.1:c.-36-5289A>C

NM_001354627.1:c.-36-5289A>C

NM_001354628.1:c.923A>C

NM_001354629.1:c.824A>C

NM_001354630.1:c.923A>C

NM_001167617.3:c.629A>C

NM_001167618.3:c.200A>C

NM_001167619.3:c.200A>C

NM_001258271.2:c.923A>C

NM_001258273.2:c.200A>C

NM_001258274.3:c.200A>C

NM_001354615.2:c.200A>C

NM_001354616.2:c.200A>C

NM_001354617.2:c.200A>C

NM_001354618.2:c.200A>C

NM_001354619.2:c.200A>C

NM_001354620.2:c.629A>C

NM_001354621.2:c.-101A>C

NM_001354622.2:c.-101A>C

NM_001354623.2:c.-101A>C

NM_001354624.2:c.-36-5289A>C

NM_001354625.2:c.-36-5289A>C

NM_001354626.2:c.-36-5289A>C

NM_001354627.2:c.-36-5289A>C

NM_001354628.2:c.923A>C

NM_001354629.2:c.824A>C

NM_001354630.2:c.923A>C

Pathogenic

PM2_Supporting PS3 PP1_Strong PP3_Moderate

Evidence Links 0

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The NM_000249.4(MLH1):c.923A>C (p.His308Pro) variant in MLH1 has a CIMRA Functional Odds for Pathogenicity of 69.27 (PS3). The variant has been reported to segregate with Lynch-syndrome and reaches 25.20 total segregation odds. The variant is not reported in gnomAD v4.1 (PM2_supporting). The variant has a prior probability of 0.974 (PP3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal-dominant inherited Lynch syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PS3, PP1_Strong, PP3_Moderate and PM2_supporting applied. (VCEP specifications version 1)

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting).

PS3

CIMRA Functional Odds for Pathogenicity is 69.27 which is >18.72; PS3 met

PP1_Strong

Segregation LR 25.20

PP3_Moderate

Prior probability is 0.974; Missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity >0.81 (PP3_Moderate) hci-priors.hci.utah.edu/PRIORS/

Curation History

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