ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2308A>G (p.Ile770Val) (rs63750684)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586175 SCV000149425 uncertain significance not provided 2017-08-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2308A>G at the cDNA level, p.Ile770Val (I770V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has been reported in a colorectal cancer study; however it is unclear if this variant was identified in a case or control (Farrington 1998). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as having uncertain significance (Thompson 2014). MSH2 Ile770Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile770Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, it is unclear whether MSH2 Ile770Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000217041 SCV000274423 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-11 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000524385 SCV000284146 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 770 of the MSH2 protein (p.Ile770Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs63750684, ExAC 0.02%). This variant has been reported in an individual who was likely a healthy control subject (PMID: 9718327). This same individual has also been reported in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 90955). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH2 gene (PMID: 22290698), all suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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.
Illumina Clinical Services Laboratory,Illumina RCV000076457 SCV000430934 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000410216 SCV000489315 uncertain significance Lynch syndrome I 2016-09-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586175 SCV000696244 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2308A>G (p.Ile770Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). Ile770 is a conserved amino acid across vertebrates and is located in P-loop containing nucleoside triphosphate hydrolase domain in the C-terminal of the DNA mismatch repair protein Msh2. Yeast homologous residue I789V had a mutator phenotype comparable to WT in forward mutator assays [Bitter 2008 patent]. This variant was found in 3/121438 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant was identified as a somatic variant in a ganglioglioma, but has not been cited as a germline variant in patients reported in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586175 SCV000888220 uncertain significance not provided 2019-06-14 criteria provided, single submitter clinical testing
Color RCV000217041 SCV000903074 likely benign Hereditary cancer-predisposing syndrome 2016-04-20 criteria provided, single submitter clinical testing

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