ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3019T>C (p.Trp1007Arg)

dbSNP: rs1553414398
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000580511 SCV000685346 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-21 criteria provided, single submitter clinical testing This missense variant replaces tryptophan with arginine at codon 1007 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 MSH6-related disorders in the literature. This variant has not been identified 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.
Mendelics RCV000708885 SCV000837907 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001060489 SCV001225181 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-08-19 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1007 of the MSH6 protein (p.Trp1007Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 489995). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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 RCV000580511 SCV002754273 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-08 criteria provided, single submitter clinical testing The p.W1007R variant (also known as c.3019T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 3019. The tryptophan at codon 1007 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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