ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2963G>T (p.Arg988Leu) (rs115386788)

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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 RCV000223636 SCV000273028 uncertain significance Hereditary cancer-predisposing syndrome 2014-11-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000465720 SCV000551292 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 988 of the MSH6 protein (p.Arg988Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs115386788, ExAC 0.04%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 229716). 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. However, an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be tolerated. 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.
Color RCV000223636 SCV000685339 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589846 SCV000695834 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2963G>T (p.Arg988Leu) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). Arg988 is located in the core and clamp domains of the DNA mismatch repair protein Msh6 protein. However, this variant has not been evaluated for functional impact by in vivo/vitro studies. This variant was found in 4/113780 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0003906 (4/10240). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. It has not, to our knowledge, been reported in affected individuals via publications. In addition, one clinical diagnostic laboratory classified this variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Mendelics RCV000708883 SCV000837905 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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