Submissions for variant NM_000251.3(MSH2):c.1070A>C (p.Glu357Ala)

gnomAD frequency: 0.00002  dbSNP: rs150503781

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168008	SCV000218659	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 357 of the MSH2 protein (p.Glu357Ala). This variant is present in population databases (rs150503781, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian, fallopian tube, or peritoneal carcinoma (PMID: 22006311). ClinVar contains an entry for this variant (Variation ID: 188133). 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.
GeneDx	RCV000236761	SCV000293020	uncertain significance	not provided	2021-08-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21120944, 18822302)
Ambry Genetics	RCV000568153	SCV000662280	likely benign	Hereditary cancer-predisposing syndrome	2022-09-20	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	RCV000568153	SCV000684901	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with alanine at codon 357 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 an individual affected with mismatch repair stable ovarian, fallopian or peritoneal cancer (PMID: 22006311). This variant has been identified in 1/251408 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.
Counsyl	RCV000662371	SCV000784764	uncertain significance	Lynch syndrome 1	2017-11-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553594	SCV001774501	uncertain significance	not specified	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1070A>C (p.Glu357Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251408 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1070A>C has been reported in the literature as a benign variant in the setting of multigene panel testing in a cohort of individuals affected with primary ovarian, peritoneal, or fallopian tube carcinoma (example, Walsh_2011). This individual was reported to have a MSI-stable tumor with a normal IHC MSI panel and loss of heterozygosity (LOH) of the variant allele was observed. These report(s) do 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000662371	SCV002526004	uncertain significance	Lynch syndrome 1	2022-05-31	criteria provided, single submitter	clinical testing	The MSH2 c.1070A>C (p.Glu357Ala) missense change has a maximum subpopulation frequency 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant was reported in one individual with a primary ovarian, peritoneal, or fallopian tube carcinoma. The tumor was further examined and showed LOH with loss of the variant allele, microsatellite stability (MSS), and normal protein expression of MLH1, MSH2, MSH6, and PMS2 on immunohistochemistry (PMID: 22006311). This variant was not observed in 157 colorectal cancer or polyp cases in one study but was observed in one control individual (PMID: 30267214). In summary, the evidence currently available is insufficient to determine the role of this variant in Lynch syndrome and constitutional mismatch repair deficiency. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV000662371	SCV004018272	uncertain significance	Lynch syndrome 1	2023-03-17	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662371	SCV004196304	uncertain significance	Lynch syndrome 1	2023-08-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995602	SCV004827076	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with alanine at codon 357 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 an individual affected with mismatch repair stable ovarian, fallopian or peritoneal cancer (PMID: 22006311). This variant has been identified in 1/251408 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.