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.1748A>G (p.Asn583Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA019161

41645 (ClinVar)

Gene: MSH2

Condition: Lynch syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3caeeba8-927f-4038-995e-ba520590df07

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000251.3:c.1748A>G

NM_000251.3(MSH2):c.1748A>G (p.Asn583Ser)

NC_000002.12:g.47471051A>G

CM000664.2:g.47471051A>G

NC_000002.11:g.47698190A>G

CM000664.1:g.47698190A>G

NC_000002.10:g.47551694A>G

NG_007110.2:g.72928A>G

ENST00000644900.2:c.1748A>G

ENST00000233146.7:c.1748A>G

ENST00000543555.6:c.1550A>G

ENST00000644092.1:c.*48A>G

ENST00000645339.1:c.1748A>G

ENST00000645506.1:c.1748A>G

ENST00000646415.1:c.1748A>G

ENST00000233146.6:c.1748A>G

ENST00000406134.5:c.1748A>G

ENST00000543555.5:c.1550A>G

ENST00000610696.4:c.*144A>G

ENST00000613514.4:c.*288A>G

ENST00000617333.3:c.*514A>G

ENST00000617938.4:c.*720A>G

ENST00000621359.2:c.1748A>G

NM_000251.2:c.1748A>G

NM_001258281.1:c.1550A>G

Likely Benign

BP4 BS3

BP5 BA1 PM2 BS2 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.1748A>G variant is predicted as a missense variant, p.(Asn583Ser). It has been identified at an MCAF 95% of 0.00934% in gnomAD all non-cancer v2.1.1 and Grpmax AF of 0.007999% in gnomAD v4.1. It is not predicted to affect protein function (Prior_utah (MAPP/PP2 < than 0.11; BP4). The variant did not affect the splicing (pCAS minigene [Pascaline Gaildrat & Stephanie Baert-Desurmont]) and showed proficient function in a calibrated functional assay (PMID 33357406; BS3). The variant was found in a patient with CRC showing MSS/IHC normal (FHCRC CCFR, Insight database). According to the current guidelines, the variant is classified as likely benign. (VCEP specifications version 1)

BP4

It is not predicted to affect protein function (Prior_utah (MAPP/PP2) = 0.000107375002699 which is < than 0.11). Moreover, it is not predicted to affect splicing (max value SpliceAI 0 and Prior_utah_splicing_de_novo = 0.02).

BS3

No effect on splicing (pCAS minigene [Pascaline Gaildrat & Stephanie Baert-Desurmont]). Proficient function in 1 calibrated assay (loss of function score -1,96 in Jia 2021; PMID 33357406; BS3)

BP5

1 patient with CRC showing MSS/IHC normal (FHCRC CCFR, Insight database)

BA1

Allelic frequency in gnomAD all non-cancer v2.1.1 = 0.09336%; MCAF 95% = 0.00934%.

PM2

Allelic frequency in gnomAD all non-cancer v2.1.1 = 0.09336% and gnomAD v4.1 Grpmax AF = 0.007999%

BS2

Co-observation with pathogenic variants in MLH1: MLH1 c.1852_1854del p.(Lys618del) (CRC age <50 Marseille UMD db entry); MLH1 c.589-1G>T (CRC age 35 Wagner et al., 2003, Chao et al., 2008).

BS1

Allelic frequency in gnomAD all non-cancer v2.1.1 = 0.09336%; MCAF 95% = 0.00934%. Allelic frequency in Bridges consortium: 11/53461 controls = 0.02% (PMID 33471991).

Curation History

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