Submissions for variant NM_000251.3(MSH2):c.716A>G (p.Gln239Arg)

gnomAD frequency: 0.00001  dbSNP: rs199676483

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656873	SCV000211225	uncertain significance	not provided	2022-04-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer (Raskin 2017); This variant is associated with the following publications: (PMID: 29212164, 31159747, 18822302, 21120944)
Invitae	RCV000198252	SCV000254427	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000411135	SCV000488394	uncertain significance	Lynch syndrome 1	2016-03-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491808	SCV000580504	benign	Hereditary cancer-predisposing syndrome	2022-04-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Genetic Services Laboratory, University of Chicago	RCV000160626	SCV000595838	uncertain significance	not specified	2017-06-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491808	SCV000685122	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 239 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 colorectal cancer showing microsatellite stability and positive immunohistochemistry results (PMID: 29212164) and an individual referred for hereditary cancer screening (PMID: 31159747). This variant has been identified in 3/251394 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.
GeneKor MSA	RCV000491808	SCV000822056	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000708828	SCV000837821	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411135	SCV001299505	uncertain significance	Lynch syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160626	SCV001437298	uncertain significance	not specified	2020-09-14	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.716A>G (p.Gln239Arg) results in a 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 1.2e-05 in 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.716A>G has been reported in the literature in individuals with suspected Lynch Syndrome (e.g. Raskin_2017, Tsaousis_2019). These reports 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. Nine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656873	SCV002774617	uncertain significance	not provided	2021-08-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656873	SCV003808948	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411135	SCV004018295	uncertain significance	Lynch syndrome 1	2023-03-20	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.
All of Us Research Program, National Institutes of Health	RCV000708828	SCV004829016	uncertain significance	Lynch syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 239 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 colorectal cancer showing microsatellite stability and positive immunohistochemistry results (PMID: 29212164) and an individual referred for hereditary cancer screening (PMID: 31159747). This variant has been identified in 3/251394 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.