Submissions for variant NM_000251.3(MSH2):c.1148G>A (p.Arg383Gln)

gnomAD frequency: 0.00001  dbSNP: rs376934727

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000490918	SCV000580588	likely benign	Hereditary cancer-predisposing syndrome	2023-08-21	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.
Color Diagnostics, LLC DBA Color Health	RCV000490918	SCV000684909	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-13	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000490918	SCV000822042	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000704685	SCV000833643	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264478	SCV001442652	uncertain significance	not specified	2020-10-22	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1148G>A (p.Arg383Gln) results in a 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251460 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1148G>A has been reported in the literature in at least an individual with a personal or family history of breast and/or ovarian cancer (Tsaousis_2019). This report however, 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004527600	SCV004108353	uncertain significance	MSH2-related disorder	2023-06-08	criteria provided, single submitter	clinical testing	The MSH2 c.1148G>A variant is predicted to result in the amino acid substitution p.Arg383Gln. This variant was reported in an individual with a personal or family history of cancer, although pathogenicity was not established (Table S5, Tsaousis et al 2019. PubMed ID: 31159747). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47656952-G-A), and is reported as uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/428531/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004003471	SCV004827187	uncertain significance	Lynch syndrome	2023-11-28	criteria provided, single submitter	clinical testing