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.1282A>G (p.Lys428Glu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA067440

455128 (ClinVar)

Gene: MSH6

Condition: Lynch syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 02b549b2-121b-4546-b1cd-3176637cb4f4

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000179.3:c.1282A>G

NM_000179.3(MSH6):c.1282A>G (p.Lys428Glu)

NC_000002.12:g.47799265A>G

CM000664.2:g.47799265A>G

NC_000002.11:g.48026404A>G

CM000664.1:g.48026404A>G

NC_000002.10:g.47879908A>G

NG_007111.1:g.21119A>G

ENST00000411819.2:c.985A>G

ENST00000420813.6:c.985A>G

ENST00000455383.6:c.985A>G

ENST00000700004.2:c.1282A>G

ENST00000699999.1:n.1366A>G

ENST00000700000.1:c.1282A>G

ENST00000700002.1:c.1288A>G

ENST00000700003.1:c.627+3202A>G

ENST00000700004.1:c.439A>G

ENST00000234420.11:c.1282A>G

ENST00000540021.6:c.892A>G

ENST00000652107.1:c.985A>G

ENST00000673637.1:c.985A>G

ENST00000234420.9:c.1282A>G

ENST00000405808.5:c.169+8930T>C

ENST00000434234.5:c.*124+8729T>C

ENST00000445503.5:c.*629A>G

ENST00000538136.1:c.376A>G

ENST00000540021.5:c.892A>G

ENST00000614496.4:c.376A>G

ENST00000616033.4:c.1279A>G

ENST00000622629.4:c.-1815A>G

NM_000179.2:c.1282A>G

NM_001281492.1:c.892A>G

NM_001281493.1:c.376A>G

NM_001281494.1:c.376A>G

NM_001281492.2:c.892A>G

NM_001281493.2:c.376A>G

NM_001281494.2:c.376A>G

Likely Pathogenic

PM2_Supporting PS3 PP4 PP3

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 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.1282A>G variant is predicted as a missense p.(Lys428Glu) variant. Its MAPP+PolyPhen-2 prior probability for pathogenicity is >0.68 & ≤0.81 (http://priors.hci.utah.edu/PRIORS). It is extremely rare in gnomAD v2.1.1 non-cancer dataset and gnomAD v4.1 (<1 in 50,000 alleles: <0,002%). Functional defect was demonstrated by CIMRA assay (Functional Odds for Pathogenicity >18.7; Insight database). It was identified in an individual affected by colon cancer showing MSH6 loss (Insight database). Therefore, this variant is classified as likely pathogenic. (VCEP specifications version 1)

PM2_Supporting

PM2_supporting is assigned because the variant is observed at 4e-06 frequency (gnomAD v4.1: Grpmax AF = 8.400e-7 )

PS3

CIMRA assay: 6.7% (corresponds to functional odds of ~44) (Insight database)

PP4

It was identified in an individual affected by colon cancer showing MSH6 loss (Insight database). It was found in a patient diagnosed with cancer at age 41 with a family history of CRC and uterine cancer (no MSI/IHC data) (PMID: 28195393).

PP3

PP3 is met becaise prior(MAPP/PP2) is 0.7372 which is > than 0.68

Curation History

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