ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.275C>T (p.Pro92Leu)

dbSNP: rs1257646433
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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 RCV000574933 SCV000669906 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-30 criteria provided, single submitter clinical testing The p.P92L variant (also known as c.275C>T), located in coding exon 2 of the MSH6 gene, results from a C to T substitution at nucleotide position 275. The proline at codon 92 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well 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.
Mendelics RCV000708851 SCV000837863 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV000817084 SCV000957624 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-23 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 483768). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 92 of the MSH6 protein (p.Pro92Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284523 SCV001470358 uncertain significance not provided 2020-01-02 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000708851 SCV004841877 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 92 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/251470 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.

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