ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1420G>C (p.Val474Leu)

dbSNP: rs1558661621
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773765 SCV000907465 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-19 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 474 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with prostate cancer (doi: 10.1101/2021.04.15.21255554). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001373902 SCV001570641 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-15 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 474 of the MSH6 protein (p.Val474Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 629077). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Mendelics RCV003492166 SCV004232563 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing

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