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.884A>G (p.Lys295Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA016588

89573 (ClinVar)

Gene: MSH6

Condition: Lynch syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 48c7f7f9-4159-4340-bbf4-da0f9a67d227

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000179.3:c.884A>G

NM_000179.3(MSH6):c.884A>G (p.Lys295Arg)

NC_000002.12:g.47798867A>G

CM000664.2:g.47798867A>G

NC_000002.11:g.48026006A>G

CM000664.1:g.48026006A>G

NC_000002.10:g.47879510A>G

NG_007111.1:g.20721A>G

ENST00000411819.2:c.587A>G

ENST00000420813.6:c.587A>G

ENST00000455383.6:c.587A>G

ENST00000700004.2:c.884A>G

ENST00000699999.1:n.968A>G

ENST00000700000.1:c.884A>G

ENST00000700002.1:c.890A>G

ENST00000700003.1:c.627+2804A>G

ENST00000700004.1:c.41A>G

ENST00000234420.11:c.884A>G

ENST00000540021.6:c.494A>G

ENST00000652107.1:c.587A>G

ENST00000673637.1:c.587A>G

ENST00000234420.9:c.884A>G

ENST00000405808.5:c.169+9328T>C

ENST00000434234.5:c.*124+9127T>C

ENST00000445503.5:c.*231A>G

ENST00000456246.1:c.*372A>G

ENST00000538136.1:c.-23A>G

ENST00000540021.5:c.494A>G

ENST00000614496.4:c.-23A>G

ENST00000616033.4:c.881A>G

ENST00000622629.4:c.-2213A>G

NM_000179.2:c.884A>G

NM_001281492.1:c.494A>G

NM_001281493.1:c.-23A>G

NM_001281494.1:c.-23A>G

NM_001281492.2:c.494A>G

NM_001281493.2:c.-23A>G

NM_001281494.2:c.-23A>G

Uncertain Significance

BS4_Supporting

BS3 BS1 BP4 BP5 BA1 PP3 PM2

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.884A>G variant results in a missense change, p.(Lys295Arg). MCAF (95% CI) is 0.013% in GnomAD v2.1.1 and Grpmax is 0.01964% in GnomAD v4.1 (below BS1 threshold). In silico predictions are inconclusive. It has found in an individual affected by CRC showing MSH6 expression (LOVD). Lack of segregation with cancer (LR: 0.7, LOVD). Nuclear localization in DLD-1 cells (PMID 21437237). Therefore, the variant is classified as variant of unknown significance. (VCEP specifications version 1)

BS4_Supporting

Segregation LR = 0.7 (LOVD data)

BS3

Nuclear localization in DLD-1 cells (Gassman et al., 2011 PMID 21437237)

BS1

MCAF (95% CI)= 0.013% (<0.22%) in GnomAD v2.1.1

BP4

MAPP+PolyPhen-2 prior probability for pathogenicity = 0,34

BP5

1 CRC showing MSH6 expression (LOVD)

BA1

MCAF (95% CI)= 0.013% in GnomAD v2.1.1

PP3

MAPP+PolyPhen-2 prior probability for pathogenicity = 0,34

PM2

MAF 0.0093% and gnomAD v4.1 Grpmax AF = 0.01964% (not >0.022%)

Curation History

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