ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586175 SCV000149425 likely benign not provided 2020-09-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22290698, 26333163, 22949379, 18383312, 9718327, 27527004, 26810070)
Ambry Genetics RCV000217041 SCV000274423 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-27 criteria provided, single submitter clinical testing The p.I770V variant (also known as c.2308A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2308. The isoleucine at codon 770 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was reported in one of 26 healthy control individuals and was not found in any of the 50 unrelated Scottish patients diagnosed with colorectal cancer at less than 30 years of age; authors concluded this alteration was a nonpathogenic polymorphism (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep; 63(3):749-59). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000524385 SCV000284146 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-26 criteria provided, single submitter clinical testing
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000217041 SCV000903074 likely benign Hereditary cancer-predisposing syndrome 2016-04-20 criteria provided, single submitter clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000586175 SCV001749536 not provided not provided no assertion provided phenotyping only Variant interpreted as Likely benign and reported on 05-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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