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_000251.3(MSH2):c.913G>A (p.Ala305Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA022539

91243 (ClinVar)

Gene: MSH2

Condition: Lynch syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 91c34704-94d5-4631-9440-869b9a6abd69

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000251.3:c.913G>A

NM_000251.3(MSH2):c.913G>A (p.Ala305Thr)

NC_000002.12:g.47414389G>A

CM000664.2:g.47414389G>A

NC_000002.11:g.47641528G>A

CM000664.1:g.47641528G>A

NC_000002.10:g.47495032G>A

NG_007110.2:g.16266G>A

ENST00000644900.2:c.913G>A

ENST00000233146.7:c.913G>A

ENST00000543555.6:c.715G>A

ENST00000644092.1:c.913G>A

ENST00000645339.1:c.913G>A

ENST00000645506.1:c.913G>A

ENST00000646415.1:c.913G>A

ENST00000233146.6:c.913G>A

ENST00000406134.5:c.913G>A

ENST00000543555.5:c.715G>A

ENST00000610696.4:c.913G>A

ENST00000613514.4:c.913G>A

ENST00000617333.3:c.913G>A

ENST00000617938.4:c.913G>A

ENST00000621359.2:c.913G>A

NM_000251.2:c.913G>A

NM_001258281.1:c.715G>A

Likely Benign

BS3_Supporting BP5 BS4_Supporting BS2 PP3_Moderate

BS1

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 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 MSH2 c.913G>A variant is predicted as a missense variant, p.(Ala305Thr). Its MAPP+PolyPhen-2 prior probability for pathogenicity is >0.81 (http://priors.hci.utah.edu/PRIORS). It showed lack of co-segregation with disease with Bayes Likelihood Ratio >0.05 & ≤0.482 (Insight database). It was identified in 2 individuals with CRC showing MSS or inconsistent MMR protein expression pattern. It has been functionally analyzed in several studies: functional Odds for Pathogenicity is >0.05 & ≤0.482 (Drost et al., 2011 PMID 22102614); proficient function, expression and localization (PMID 18822302); proficient function (PMID 33357406). It has been identified in co-occurrence in trans with a MSH2 known pathogenic variant (Invitae internal data). Therefore, this variant is classified as likely benign.

BS3_Supporting

53% repair activity in in vitro MMR complementation assay (Drost et al., 2011 PMID 22102614). Proficient mismatch binding & ATP-dependent release; nuclear localization in localization experiments in Msh2-/- MEFs, MSH2 expression similar to WT in Western blot of hMSH2 vector expressed in Msh2 -/- MEFs (Lutzen et al., 2008. PMID 18822302). Proficient function (LoF score -5, 01; Jia et al., 2021; PMID 33357406). No effect on splicing (RT-PCR of patient RNA Arnold et al., 2009).

BP5

1 MSS (1 Wijnen et al., 1997 PMID 9311737) and 1 MSI-L/MSH2+ (1 Arnold et al., 2009 PMID 19267393)

BS4_Supporting

Segregation LR: 0.27 (Insight database)

BS2

Invitae data: Internal case with a pathogenic mutation in trans and no CMMRD phenotype

PP3_Moderate

Prior_utah (MAPP/PP2): 0.9295 which is > than 0.81

BS1

MCAF in NFE is 0.007510% (below BS1 threshold)

Curation History

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