Submissions for variant NM_000251.3(MSH2):c.1191A>T (p.Gln397His)

dbSNP: rs768694189

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210074	SCV000266189	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000482758	SCV000571926	uncertain significance	not provided	2019-07-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26845104)
Ambry Genetics	RCV000568248	SCV000662254	likely benign	Hereditary cancer-predisposing syndrome	2019-04-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000629900	SCV000750856	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 397 of the MSH2 protein (p.Gln397His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with liver cancer and polyps (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224575). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000568248	SCV000905082	likely benign	Hereditary cancer-predisposing syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267950	SCV002552221	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267950	SCV002555962	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1191A>T (p.Gln397His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1191A>T has been reported in the literature in an individual diagnosed with liver cancer under the age of 20 (example: Shirts_2016). However, Shirts_2020 authors classified the variant as VUS. This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26845104). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003468974	SCV004196172	uncertain significance	Lynch syndrome 1	2023-10-20	criteria provided, single submitter	clinical testing