Submissions for variant NM_000251.3(MSH2):c.1144C>T (p.Arg382Cys)

gnomAD frequency: 0.00003  dbSNP: rs752373431

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214618	SCV000276498	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-28	criteria provided, single submitter	clinical testing	The p.R382C variant (also known as c.1144C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1144. The arginine at codon 382 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in an individual with multiple colon polyps (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000409794	SCV000489635	uncertain significance	Lynch syndrome 1	2016-11-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000480571	SCV000566392	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with a personal and family history of colon cancer and polyps, in an individual with family history of breast/ovarian cancer, and in an individual with gastric cancer (Weren et al., 2015; Huang et al., 2018; Lerner-Ellis et al., 2021); Published functional studies suggest this variant has no damaging effect based on results of an assay measuring resistance to 6-TG (Jia et al., 2020); This variant is associated with the following publications: (PMID: 36451132, 29625052, 21120944, 18822302, 32885271, 25938944, 33357406)
Invitae	RCV000546544	SCV000625229	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214618	SCV000689955	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 382 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colonic adenomas (PMID: 25938944). This variant has been identified in 9/282852 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761006	SCV000890921	uncertain significance	Lynch syndrome	2020-10-01	criteria provided, single submitter	clinical testing	The MSH2 c.1144C>T (p.Arg382Cys) missense change has a maximal subpopulation frequency of 0.0065% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47656948-C-T). Seven of seven in silico algorithms predict a deleterious effect on the gene or gene product (PP3), however these predictions have not been confirmed by functional studies. This variant has been reported in one individual with stomach adenocarcinoma (PMID: 29625052) and one individual with colorectal cancer (PMID: 25938944). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3.
New York Genome Center	RCV000480571	SCV002025628	uncertain significance	not provided	2020-05-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409794	SCV004018215	likely benign	Lynch syndrome 1	2023-03-16	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].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387810	SCV004099692	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1144C>T (p.Arg382Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1144C>T has been reported in the literature in individuals affected with Breast/Ovarian cancer (Dorling_2021, Lerner-Ellis_2021), Colorectal Cancer (Weren_2015) and Stomach Cancer (Huang_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. A cell-based assay using MSH2 deficient HAP1 cells suggest that the variant confers resistance to DNA damage induced by 6-thioguanine (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 29625052, 25938944, 33471991, 32885271, 33357406). Eight ClinVar submitters have assessed the variant since 2014: six classified the variant as uncertain significance, and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000409794	SCV004194555	uncertain significance	Lynch syndrome 1	2023-06-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000480571	SCV001550345	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Arg382Cys variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, Zhejiang University Database, or the Mismatch Repair Genes Variant database. The variant was identified in dbSNP (ID: rs752373431) as "With Uncertain significance allele ", in ClinVar (classified as uncertain significance by Ambry Genetics, Counsyl, GeneDx, Invitae, Color Genomics), UMD-LSDB (1x as unclassified variant), and in Insight Hereditary Tumors database (1x). The variant was identified in control databases in 9 of 277218 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), Other in 1 of 6466 chromosomes (freq: 0.0002), European in 4 of 126704 chromosomes (freq: 0.00003), East Asian in 1 of 18870 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.0001); it was not observed in the Latino, Ashkenazi Jewish, and Finnish populations. The p.Arg382 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.