Submissions for variant NM_000251.3(MSH2):c.1774A>G (p.Met592Val)

gnomAD frequency: 0.00005  dbSNP: rs371614039

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656879	SCV000211190	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of colorectal or breast cancer, as well as in unaffected control groups (Nilbert et al., 2009; Chubb et al., 2015; Wu et al., 2019; Akcay et al., 2020; Bandeira et al., 2021; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26333163, 18383312, 18566915, 16995940, 25559809, 22290698, 23690608, 32986223, 33471991, 32658311, 31391288, 31569399, 18822302, 21120944, 9774676)
Ambry Genetics	RCV000160595	SCV000212842	likely benign	Hereditary cancer-predisposing syndrome	2018-08-15	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	RCV000524360	SCV000261045	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212609	SCV000539690	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 3VUS (including expert panel), no new evidence since expert classification
Color Diagnostics, LLC DBA Color Health	RCV000160595	SCV000684975	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 592 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 breast cancer (PMID: 31569399, 32658311, 32986223, 33471991), colorectal cancer (PMID: 25559809, 32658311), unspecified cancer (PMID: 31391288), and in a family affected with Lynch syndrome (PMID: 18566915). This variant has also been reported in numerous healthy individuals (PMID: 32658311, 33471991). This variant has been identified in 8/282822 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	RCV000662460	SCV000784941	uncertain significance	Lynch syndrome 1	2017-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212609	SCV001623207	uncertain significance	not specified	2022-09-01	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1774A>G (p.Met592Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251442 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1774A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer(example: Nilbert_2009, Drost_2013, Chubb_2015, Wu_2019, Ackay_2021, Banderia_2021 etc.). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with a pathogenic variant classified by our laboratory has been reported (BRCA1 c.5096G>A, p.R1699Q), providing supporting evidence for a benign role. In addition, a recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021, LOVD database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar classifying as VUS (n=9) and likely benign (n=1) Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656879	SCV002049510	uncertain significance	not provided	2021-08-18	criteria provided, single submitter	clinical testing	The MSH2 c.1774A>G p.Met592Val variant (rs371614039) is reported in the literature in two individuals with a personal and family history of cancer (Nilbert 2009, Chubb 2015). This variant is also reported in ClinVar (Variation ID: 90782). The variant is found in the Non-Finnish European population with an allele frequency of 0.006% (8/129158 alleles) in the Genome Aggregation Database. The Methionine at codon 592 is moderately conserved and computational analyses predict that this variant is uncertain (REVEL: 0.383). Due to limited information, the clinical significance of the MSH2 c.1774A>G p.Met592Val variant is uncertain at this time.
CeGaT Center for Human Genetics Tuebingen	RCV000656879	SCV002496482	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	MSH2: PS3:Supporting
Sema4, Sema4	RCV000160595	SCV002534410	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212609	SCV002552242	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662460	SCV004018370	likely benign	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000662460	SCV004193907	uncertain significance	Lynch syndrome 1	2023-10-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656879	SCV004220957	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with Lynch syndrome (PMID: 18566915 (2009)), colorectal cancer (PMID: 25559809 (2015), 31391288 (2020), 32658311 (2021)), and breast cancer (PMID: 31569399 (2019), 32658311 (2021), 32986223 (2021), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH2)). This variant has also been reported in unaffected individuals (PMID: 32658311 (2021), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH2)). The frequency of this variant in the general population, 0.00062 (3/4824 chromosomes in Estonian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997153	SCV004827311	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 592 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 breast cancer (PMID: 31569399, 32658311, 32986223, 33471991), colorectal cancer (PMID: 25559809, 32658311), unspecified cancer (PMID: 31391288), and in a family affected with Lynch syndrome (PMID: 18566915). This variant has also been reported in numerous healthy individuals (PMID: 32658311, 33471991). This variant has been identified in 8/282822 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357833	SCV001553420	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Met592Val variant was identified in 3 of 3368 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch syndrome or colorectal cancer (Chubb 2015, Nilbert 2009). The variant was also identified in dbSNP (ID: rs371614039) as "With other allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx and four other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 8 of 277192 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 8 of 126706 chromosomes (freq: 0.00006), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Met592 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.