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_000179.3(MSH6):c.1296T>G (p.Phe432Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA337394

216294 (ClinVar)

Gene: MSH6

Condition: Lynch syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 26c469ab-9ecd-448d-bb87-5e193d048eec

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000179.3:c.1296T>G

NM_000179.3(MSH6):c.1296T>G (p.Phe432Leu)

NC_000002.12:g.47799279T>G

CM000664.2:g.47799279T>G

NC_000002.11:g.48026418T>G

CM000664.1:g.48026418T>G

NC_000002.10:g.47879922T>G

NG_007111.1:g.21133T>G

ENST00000411819.2:c.999T>G

ENST00000420813.6:c.999T>G

ENST00000455383.6:c.999T>G

ENST00000700004.2:c.1296T>G

ENST00000699999.1:n.1380T>G

ENST00000700000.1:c.1296T>G

ENST00000700002.1:c.1302T>G

ENST00000700003.1:c.627+3216T>G

ENST00000700004.1:c.453T>G

ENST00000234420.11:c.1296T>G

ENST00000540021.6:c.906T>G

ENST00000652107.1:c.999T>G

ENST00000673637.1:c.999T>G

ENST00000234420.9:c.1296T>G

ENST00000405808.5:c.169+8916A>C

ENST00000434234.5:c.*124+8715A>C

ENST00000445503.5:c.*643T>G

ENST00000538136.1:c.390T>G

ENST00000540021.5:c.906T>G

ENST00000614496.4:c.390T>G

ENST00000616033.4:c.1293T>G

ENST00000622629.4:c.-1801T>G

NM_000179.2:c.1296T>G

NM_001281492.1:c.906T>G

NM_001281493.1:c.390T>G

NM_001281494.1:c.390T>G

NM_001281492.2:c.906T>G

NM_001281493.2:c.390T>G

NM_001281494.2:c.390T>G

Likely Pathogenic

PM2_Supporting PS3 PP3

Evidence Links 1

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 MSH6 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 MSH6 c.1296T>G is a missense variant predicted to cause substitution of Phenylalanine to Leucine at amino acid 432 (p.Phe432Leu). The prior probability for pathogenicity of this missense variant is 0.7 according to hci-priors.hci.utah.edu/PRIORS/ (PP3). Functional odds (CIMRA assay) of 45.743 supports evidence of pathogenicity of the variant (PS3). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PS3, PP3 and PM2_Sup (VCEP specifications version 1)

PM2_Supporting

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

PS3

Functional odds: 45.743 (CIMRA Functional Odds for Pathogenicity >18.7)

Supplementary material. Table S5: p.F432L CIMRA functional odds: 45.743 PubMed:31965077

PP3

The prior probability of the missense variant is 0.70 (hci-priors.hci.utah.edu/PRIORS/), which is within the thresholds of 0.68 to 0.81

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.