ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2203A>G (p.Ile735Val) (rs2229061)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411526 SCV000488460 uncertain significance Lynch syndrome I 2016-04-07 criteria provided, single submitter clinical testing
Invitae RCV000471467 SCV000548318 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 735 of the MSH2 protein (p.Ile735Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs2229061, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 161300). Experimental studies have shown that this missense change does not impact mismatch repair activity (PMID: 26951660). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000588732 SCV000568635 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2203A>G at the cDNA level, p.Ile735Val (I735V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant was observed in a large cohort of unselected epithelial ovarian cancer cases (Pal 2012). MSH2 Ile735Val was evaluated in a mouse embryonic stem cell assay, and was demonstrated to not negatively impact mismatch repair activity (Houlleberghs 2016). MSH2 Ile735Val was observed at an allele frequency of 0.05% (12/24,026) in individuals of African ancestry in large population cohorts (Lek 2016). MSH2 Ile735Val is located in the ATPase domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Ile735Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491584 SCV000580512 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing Conflicting evidence
Color RCV000491584 SCV000685020 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175338 SCV000696237 uncertain significance not specified 2019-10-21 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2203A>G (p.Ile735Val) results in a conservative amino acid change located in the C-terminal domain (IPR000432) 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 1.3 fold the estimated maximal pathogenic allele frequency expected for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), 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 without strong evidence for causality (e.g. Pal_2012, Shi_2016, Deng_2019, Kiyozumi_2019, Yoo_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One publication reports experimental evidence suggesting that the variant does not impact mismatch repair in a screen for mismatch repair-deficient cells following oligo-targeting in mouse embryonic stem cells (Houlleberghs_2016). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign variant.
Mendelics RCV000411526 SCV001135752 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148638 SCV000190353 uncertain significance Ovarian cancer 2014-06-01 no assertion criteria provided research

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