ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1301C>T (p.Ala434Val) (rs768070717)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232170 SCV000284104 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 434 of the MSH2 protein (p.Ala434Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs768070717, ExAC 0.002%). This variant has been observed in individual(s) with pancreatic cancer (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 237365). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000573477 SCV000673892 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000589179 SCV000696206 uncertain significance not provided 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1301C>T (p.Ala434Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/119796 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). In addition, one diagnostic laboratory has classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV000573477 SCV001349064 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-05 criteria provided, single submitter clinical testing

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