ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1574G>C (p.Ser525Thr)

dbSNP: rs765387680
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001189349 SCV001356615 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-08 criteria provided, single submitter clinical testing This missense variant replaces serine with threonine at codon 525 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251322 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Neuberg Centre For Genomic Medicine, NCGM RCV004789452 SCV005400956 uncertain significance Lynch syndrome 5 2023-06-22 criteria provided, single submitter clinical testing The observed missense variant c.1574G>C(p.Ser525Thr) in the MSH6 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Ser at position 525 is changed to a Thr changing protein sequence and it might alter its composition and physico- chemical properties. Computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predicts conflicting evidence on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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