Submissions for variant NM_000251.3(MSH2):c.965G>T (p.Gly322Val)

dbSNP: rs4987188

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131668	SCV000186696	likely benign	Hereditary cancer-predisposing syndrome	2022-10-26	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	RCV000203979	SCV000260822	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000410421	SCV000489132	uncertain significance	Lynch syndrome 1	2016-08-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000482522	SCV000569289	uncertain significance	not provided	2023-04-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19698169, 31159747, 31592449, 18822302, 21120944, 34646395)
Color Diagnostics, LLC DBA Color Health	RCV000131668	SCV000685144	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 322 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 individuals affected with breast cancer (PMID: 34646395; DOI: 10.1101/2021.04.15.21255554), and in an individual affected with breast and lung cancer (PMID: 31592449). 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.
GeneKor MSA	RCV000131668	SCV000822057	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000410421	SCV002579013	uncertain significance	Lynch syndrome 1	2022-04-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410421	SCV004018288	likely benign	Lynch syndrome 1	2023-03-20	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	RCV000410421	SCV004196222	uncertain significance	Lynch syndrome 1	2023-10-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000482522	SCV004698535	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MSH2: BP1, BS3:Supporting
All of Us Research Program, National Institutes of Health	RCV001357874	SCV004824476	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 322 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 individuals affected with breast cancer (PMID: 34646395; DOI: 10.1101/2021.04.15.21255554), and in an individual affected with breast and lung cancer (PMID: 31592449). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357874	SCV001553467	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Gly322Val variant was not identified in the literature nor was it identified in the UMD-LSDB. The variant was identified in dbSNP (ID: rs4987188) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and four other submitters). The variant was identified in control databases in 7 of 246202 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 7 of 111668 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gly322 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Genetic Services Laboratory, University of Chicago	RCV003150951	SCV003839740	uncertain significance	not specified	2022-12-14	no assertion criteria provided	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.965G>T, in exon 6 that results in an amino acid change, p.Gly322Val. This sequence change has been previously described in individuals with breast cancer and lung cancer however its impact on disease was not certain (PMID: 34646395, 31592449). This sequence change has been described in the gnomAD database with a frequency of 0.004% in the European subpopulation (dbSNP rs4987188). The p.Gly322Val change affects a moderately conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly322Val substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly322Val change remains unknown at this time.