Submissions for variant NM_000251.3(MSH2):c.2203A>G (p.Ile735Val)

gnomAD frequency: 0.00011  dbSNP: rs2229061

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411526	SCV000488460	uncertain significance	Lynch syndrome 1	2016-04-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471467	SCV000548318	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000588732	SCV000568635	likely benign	not provided	2019-05-17	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 26951660, 22949387, 23047549, 29192238, 30833958, 31386297)
Ambry Genetics	RCV000491584	SCV000580512	benign	Hereditary cancer-predisposing syndrome	2021-08-12	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.
Color Diagnostics, LLC DBA Color Health	RCV000491584	SCV000685020	likely benign	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175338	SCV000696237	likely benign	not specified	2023-11-13	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2203A>G (p.Ile735Val) results in a conservative amino acid change located in the in the C-terminal domain (IPR000432) and ATP-binding cassette domain (IPR032642) of 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 6e-05 in 251638 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2203A>G has been reported in the literature in individuals affected with cancer including colorectal cancer, ovarian cancer, breast cancer, endometrial cancer, prostate cancer and esophageal squamous cell carcinoma (e.g. Pal_2012, Yehia_2018, Deng_2019, Kiyozumi_2019, Tian_2019, Wei_2019, Fujita_2022), however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least two publications report experimental evidence suggesting that the variant does not disrupt mismatch repair activity and is a functionally neutral substitution (e.g., Houlleberghs_2016, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 30833958, 33309985, 26951660, 33357406, 31386297, 12376507, 23047549, 30122538, 27974047, 22949387, 31054147, 31248605, 29684080, 31235699). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (benign, n = 2; likely benign, n = 2; VUS, n = 4). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000411526	SCV001135752	uncertain significance	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001175338	SCV002552257	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411526	SCV004018313	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].
PreventionGenetics, part of Exact Sciences	RCV004532667	SCV004116332	uncertain significance	MSH2-related disorder	2023-07-13	criteria provided, single submitter	clinical testing	The MSH2 c.2203A>G variant is predicted to result in the amino acid substitution p.Ile735Val. This variant has been reported in individuals with ovarian cancer, esophageal cancer, an unspecified cancer type (Table 2, Pal et al. 2012. PubMed ID: 23047549; Table S2, Deng et al. 2019. PubMed ID: 30833958; Table S1, Kiyozumi et al. 2019. PubMed ID: 31386297). In vitro experimental studies suggest that this variant does not result in loss of protein function (Tables S3 and S4, Jia et al. 2020. PubMed ID: 33357406). In silico tools predictions for this variant are conflicting (Table 2, Pal et al. 2012. PubMed ID: 23047549; Table 2, Thompson et al. 2012. PubMed ID: 22949387; Tables S3 and S4, Jia et al. 2020. PubMed ID: 33357406). This variant is reported in 0.056% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47703703-A-G; Table S1, Amendola et al. 2015. PubMed ID: 25637381). It has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/161300/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CSER _CC_NCGL, University of Washington	RCV000148638	SCV000190353	uncertain significance	Ovarian cancer	2014-06-01	no assertion criteria provided	research