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 2018-12-16 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 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000491584 SCV000685020 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588732 SCV000696237 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Variant summary: Variant affects a conserved nucleotide and results in a replacement of a replacement of an Isoleucine (I) with a Valine (V). Both residues are medium size and hydrophobic, therefore this Isoleucine to Valine substitution likely does not alter the physico-chemical properties of the protein. 3/4 in silico tools predict the variant to be damaging. It was observed predominantly in the African subcohort of the ExAC project at an allele frequency of 0.077% which slightly exceeds the maximal expected allele frequency of a disease causing MSH2 allele (0.056%). The variant was reported in one epithelial ovarian cancer, however without strong evidence for pathogenicity. To our knowledge, studies assessing the impact the variant may have on MSH2 function were not published at the time of scoring. One clinical diagnostic center lists variant as Uncertain (without evidence to independently evaluate). Due to the lack of stronger clinical information and lack of functional studies the variant was classified as a variant of uncertain significance until more information becomes available.
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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