ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1043A>G (p.Gln348Arg) (rs773177076)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167409 SCV000218264 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000410781 SCV000487993 uncertain significance Lynch syndrome I 2015-12-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586839 SCV000696196 uncertain significance not provided 2016-09-26 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1043A>G (p.Gln348Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121392 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. One clinical diagnostic laboratory classified this variant as uncertain significance. 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.
Invitae RCV000700524 SCV000829282 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 348 of the MSH2 protein (p.Gln348Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs773177076, ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 187660). 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 disruptive, 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.
Color RCV000167409 SCV000908291 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing

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