Submissions for variant NM_000251.3(MSH2):c.964G>A (p.Gly322Ser)

gnomAD frequency: 0.00002  dbSNP: rs773301485

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167081	SCV000217909	likely benign	Hereditary cancer-predisposing syndrome	2023-02-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199307	SCV000254433	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588197	SCV000696294	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.964G>A (p.Gly322Ser) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/121144 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000167081	SCV000908288	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 322 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with uterine cancer (PMID: 29684080). This variant has been identified in 5/251428 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000167081	SCV002526781	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	curation
GeneDx	RCV000588197	SCV003921733	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal history of uterine cancer (Yehia et al., 2018); Published functional studies suggest no damaging effect: mismatch repair (MMR) function similar to wildtype (Jia et al., 2020); This variant is associated with the following publications: (PMID: 27720647, 18822302, 21120944, 29684080, 33357406)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167081	SCV004014918	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468799	SCV004196317	uncertain significance	Lynch syndrome 1	2023-08-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995555	SCV004824465	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 322 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with uterine cancer (PMID: 29684080). This variant has been identified in 5/251428 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.