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.350C>G (p.Thr117Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA009864

90178 (ClinVar)

Gene: MLH1

Condition: Lynch syndrome 1

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ec108f66-c6db-418a-9692-4649aa3250cb

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.350C>G

NM_000249.4(MLH1):c.350C>G (p.Thr117Arg)

NC_000003.12:g.37004444C>G

CM000665.2:g.37004444C>G

NC_000003.11:g.37045935C>G

CM000665.1:g.37045935C>G

NC_000003.10:g.37020939C>G

NG_007109.2:g.16095C>G

ENST00000413740.2:c.350C>G

ENST00000429117.6:c.56C>G

ENST00000450420.6:c.350C>G

ENST00000456676.7:c.350C>G

ENST00000458009.6:c.350C>G

ENST00000492474.6:c.-374C>G

ENST00000616768.6:c.350C>G

ENST00000673673.2:c.350C>G

ENST00000231790.8:c.350C>G

ENST00000413212.2:c.-374C>G

ENST00000432299.6:c.*430C>G

ENST00000441265.6:c.-374C>G

ENST00000442249.6:n.365C>G

ENST00000447829.6:c.18-2547C>G

ENST00000539477.6:c.-282C>G

ENST00000673673.1:c.303C>G

ENST00000673713.1:n.381C>G

ENST00000673715.1:c.350C>G

ENST00000673897.1:c.*142C>G

ENST00000673899.1:c.350C>G

ENST00000673947.1:c.*490C>G

ENST00000673972.1:c.*228C>G

ENST00000673990.1:n.335C>G

ENST00000674019.1:c.-374C>G

ENST00000674107.1:n.292C>G

ENST00000674111.1:c.350C>G

ENST00000231790.6:c.350C>G

ENST00000429117.5:c.56C>G

ENST00000432299.5:c.*430C>G

ENST00000435176.5:c.56C>G

ENST00000441265.5:c.-282C>G

ENST00000442249.5:c.*142C>G

ENST00000454028.5:c.*223C>G

ENST00000455445.6:c.-374C>G

ENST00000456676.6:c.325C>G

ENST00000457004.5:c.*129C>G

ENST00000458205.6:c.-374C>G

ENST00000466900.5:n.277C>G

ENST00000485889.1:n.354C>G

ENST00000492474.5:n.373C>G

ENST00000536378.5:c.-374C>G

ENST00000539477.5:c.-282C>G

NM_000249.3:c.350C>G

NM_001167617.1:c.56C>G

NM_001167618.1:c.-374C>G

NM_001167619.1:c.-282C>G

NM_001258271.1:c.350C>G

NM_001258273.1:c.-374C>G

NM_001258274.1:c.-374C>G

NM_001167617.2:c.56C>G

NM_001167618.2:c.-374C>G

NM_001167619.2:c.-282C>G

NM_001258274.2:c.-374C>G

NM_001354615.1:c.-282C>G

NM_001354616.1:c.-282C>G

NM_001354617.1:c.-374C>G

NM_001354618.1:c.-374C>G

NM_001354619.1:c.-374C>G

NM_001354620.1:c.56C>G

NM_001354621.1:c.-467C>G

NM_001354622.1:c.-580C>G

NM_001354623.1:c.-580C>G

NM_001354624.1:c.-477C>G

NM_001354625.1:c.-385C>G

NM_001354626.1:c.-477C>G

NM_001354627.1:c.-477C>G

NM_001354628.1:c.350C>G

NM_001354629.1:c.251C>G

NM_001354630.1:c.350C>G

NM_001167617.3:c.56C>G

NM_001167618.3:c.-374C>G

NM_001167619.3:c.-282C>G

NM_001258271.2:c.350C>G

NM_001258273.2:c.-374C>G

NM_001258274.3:c.-374C>G

NM_001354615.2:c.-282C>G

NM_001354616.2:c.-282C>G

NM_001354617.2:c.-374C>G

NM_001354618.2:c.-374C>G

NM_001354619.2:c.-374C>G

NM_001354620.2:c.56C>G

NM_001354621.2:c.-467C>G

NM_001354622.2:c.-580C>G

NM_001354623.2:c.-580C>G

NM_001354624.2:c.-477C>G

NM_001354625.2:c.-385C>G

NM_001354626.2:c.-477C>G

NM_001354627.2:c.-477C>G

NM_001354628.2:c.350C>G

NM_001354629.2:c.251C>G

NM_001354630.2:c.350C>G

Likely Pathogenic

PP1_Moderate PP4_Moderate PM2_Supporting PM5 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:c.350C>G variant in MLH1 is a missense variant predicted to cause substitution of Threonin by Arginin at amino acid 117 (p.Thr117Arg). Criteria PM5 is met since p.(Thr117Arg) is a missense change at an amino acid residue where a different missense change was classified by this VCEP as pathogenic on the protein level and not due to aberrant splicing (p.Thr117Met is InSiGHT class 5). The variant is not reported in gnomAD v2.1 and once in gnomAD v4.1 (PM2_supporting). Co-segregation studies showed segragation with disease in pedigree(s) with a combined Bayes Likelihood Ratio >2.08 & ≤4.32 (PP1). The prior probability is 0.948 (PP3_moderate). The variant was detected in 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM5, PM2_SUP, PP1, PP3, PP4 (VCEP specifications version 1)

PP1_Moderate

Total segregation odds: 15.30 (PP1_moderate)

PP4_Moderate

2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location

PM2_Supporting

The variant is not reported in gnomAD v2.1 and once in gnomAD v4.1 (PM2_supporting)

PM5

Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Change p.Thr117Met is InSiGHT class 5 (PM5)

PP3_Moderate

prio probability is 0.948 (PP3_moderate) hci-priors.hci.utah.edu/PRIORS/

Curation History

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