Submissions for variant NM_000251.3(MSH2):c.409G>C (p.Gly137Arg)

gnomAD frequency: 0.00003  dbSNP: rs587781795

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130057	SCV000184884	likely benign	Hereditary cancer-predisposing syndrome	2019-12-09	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	RCV000196356	SCV000254423	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000679311	SCV000257189	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	BS3_supporting
GeneDx	RCV000679311	SCV000292616	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	Published functional studies suggest a neutral effect: restored mismatch repair (MMR) function in a MSH2 knockout cell line (PMID: 33357406); Observed in individuals with uterine or breast cancer (PMID: 34326862); 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: 31391288, 35676339, 18822302, 21120944, 33357406, 34326862)
Genetic Services Laboratory, University of Chicago	RCV000202282	SCV000595834	uncertain significance	not specified	2017-03-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202282	SCV000601477	uncertain significance	not specified	2017-04-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130057	SCV000690108	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 137 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 an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 7/282736 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798439	SCV002042108	uncertain significance	Breast and/or ovarian cancer	2023-04-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130057	SCV002534520	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-11	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003997545	SCV004830199	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 137 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 an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 7/282736 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.
PreventionGenetics, part of Exact Sciences	RCV004734672	SCV000806041	uncertain significance	MSH2-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The MSH2 c.409G>C variant is predicted to result in the amino acid substitution p.Gly137Arg. This variant has been reported in one patient from a cohort of individuals with cancer and microsatellite instability (MSI) (Table S4. Li et al 2019. PubMed ID: 31391288). It was also seen in one patient with uterine cancer and a family history suggestive of an hereditary cancer syndrome (Table S4. Bhai et al 2021. PubMed ID: 34326862). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance by most submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141500/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355466	SCV001550359	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Gly137Arg variant was not identified in the literature nor was it identified in the Gene Insight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587781795 as "With other allele") and ClinVar (1x as likely benign by Ambry Genetics and 6x as uncertain significance by GeneDx, Color Genomics, Invitae, and three other clinical laboratories). The variant was identified in control databases in 6 of 277190 chromosomes (1 homozygous) at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 6 of 126680 chromosomes (freq: 0.00005), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gly137 residue is not 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 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.