Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000251.3(MSH2):c.1012G>A (p.Gly338Arg)

CA016843

90503 (ClinVar)

Gene: MSH2
Condition: Lynch syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 00fb8e5c-5cfe-4461-b920-61e084e94eff
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000251.3:c.1012G>A
NM_000251.3(MSH2):c.1012G>A (p.Gly338Arg)
NC_000002.12:g.47416365G>A
CM000664.2:g.47416365G>A
NC_000002.11:g.47643504G>A
CM000664.1:g.47643504G>A
NC_000002.10:g.47497008G>A
NG_007110.2:g.18242G>A
ENST00000644900.2:c.1012G>A
ENST00000233146.7:c.1012G>A
ENST00000543555.6:c.814G>A
ENST00000644092.1:c.1012G>A
ENST00000645339.1:c.1012G>A
ENST00000645506.1:c.1012G>A
ENST00000646415.1:c.1012G>A
ENST00000233146.6:c.1012G>A
ENST00000406134.5:c.1012G>A
ENST00000543555.5:c.814G>A
ENST00000610696.4:c.1012G>A
ENST00000613514.4:c.1012G>A
ENST00000617333.3:c.1012G>A
ENST00000617938.4:c.1012G>A
ENST00000621359.2:c.1012G>A
NM_000251.2:c.1012G>A
NM_001258281.1:c.814G>A
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Pathogenic

Met criteria codes 5
PP4_Moderate PP3_Moderate PS3 PP1 PM2_Supporting

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 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_000251.3:c.1012G>A variant in MSH2 is a missense variant predicted to cause substitution of Glycine to Arginine at amino acid 338 (p.Gly338Arg). The prior probability for pathogenicity of this missense variant is 0.96 according to http://priors.hci.utah.edu/PRIORS (PP3_moderate). This variant has been identified in at least two independent patients with CRC: one tumor with loss of MSH2 and MSH6 protein expression and one tumour with loss of MSH2 protein expression (PP4_moderate). Results of functional and segregation odds support the evidence of pathogenicity of the variant (PS3 and PP1). 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 pathogenic for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PP3_Mod, PP4_Mod, PS3, PP1 and PM2_Sup (VCEP specifications version 1)
Met criteria codes
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.
PP3_Moderate
prior probability is 0.96 (prior probability used is 0.90)
PS3
Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7)
Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7) Data_Sheet_1 PubMed:32849802
PP1
Total segregation odds: 2.37
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and gnomAD v4.1
Curation History
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