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.2075G>T (p.Gly692Val)

CA019969

90880 (ClinVar)

Gene: MSH2
Condition: Lynch syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 555cfb24-45a7-4e0d-83e2-5a7993f58ca0
Approved on: 2024-09-19
Published on: 2024-10-11

HGVS expressions

NM_000251.3:c.2075G>T
NM_000251.3(MSH2):c.2075G>T (p.Gly692Val)
NC_000002.12:g.47476436G>T
CM000664.2:g.47476436G>T
NC_000002.11:g.47703575G>T
CM000664.1:g.47703575G>T
NC_000002.10:g.47557079G>T
NG_007110.2:g.78313G>T
ENST00000644900.2:c.2075G>T
ENST00000233146.7:c.2075G>T
ENST00000543555.6:c.1877G>T
ENST00000644092.1:c.*375G>T
ENST00000645339.1:c.2075G>T
ENST00000645506.1:c.2075G>T
ENST00000646415.1:c.2075G>T
ENST00000233146.6:c.2075G>T
ENST00000406134.5:c.2075G>T
ENST00000543555.5:c.1877G>T
ENST00000610696.4:c.*471G>T
ENST00000613514.4:c.*615G>T
ENST00000617333.3:c.*841G>T
ENST00000617938.4:c.*1047G>T
ENST00000621359.2:c.2075G>T
NM_000251.2:c.2075G>T
NM_001258281.1:c.1877G>T
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Pathogenic

Met criteria codes 4
PM2_Supporting PP3_Moderate PS3 PP4_Strong

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(MSH2):c.2075G>T (p.Gly692Val) variant is a missense variant and leads to a change of Glycin to Valin at position 692. This variant has been reported in at least 3 independent CRC/Endometrial MSI-H tumours in ≥2 families using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PMID: 29212164, PMID: 21879275; ClinVar submission: VCV000090880.2) (PP4_STR met) Furthermore, the variant has been detected in a 9y old patient with CMMR-D in combination with a other pathogenic variant in MSH2/EPCAM. (PM3 met) The CIMRA functional odds is 150.82, which exceeds the threshold of 18.7 (PS3 met). The prior probability is 93.9 which exceeds the threshold of 18.7 (PP3_MOD met). The variant is not reported in gnomAD v4.1 (PM2_supporting met). In summary, this variant meets the criteria to be classified as pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PS3, PP3_MOD, PP4_STR, PM3 and PM2_supporting applied. (VCEP specifications version 1)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting).
PP3_Moderate
The prior probability the the missense variant is 0,93, which is higher than the proposed threshold of >0.81 (PP3_moderate) hci-priors.hci.utah.edu/PRIORS/
PS3
The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3).
The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3). Data_Sheet_1 PubMed:32849802
PP4_Strong
More than 3 independent CRC/Endometrial MSI-H tumours in ≥2 families using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location.
Curation History
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