ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1498G>A (p.Ala500Thr)

gnomAD frequency: 0.00006  dbSNP: rs786204127
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168089 SCV000218743 benign Hereditary nonpolyposis colorectal neoplasms 2023-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000657123 SCV000279936 uncertain significance not provided 2023-03-01 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22949387, 17531815, 21120944)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657123 SCV000601508 uncertain significance not provided 2019-03-27 criteria provided, single submitter clinical testing
GeneID Lab - Advanced Molecular Diagnostics RCV000578381 SCV000680453 uncertain significance Lynch syndrome 2017-09-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV001011904 SCV001172286 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-05 criteria provided, single submitter clinical testing The p.A500T variant (also known as c.1498G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1498. The alanine at codon 500 is replaced by threonine, an amino acid with similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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.
Color Diagnostics, LLC DBA Color Health RCV001011904 SCV001346916 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-23 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 500 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 3/282616 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.
Sema4, Sema4 RCV001011904 SCV002535629 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-15 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV000578381 SCV004839318 uncertain significance Lynch syndrome 2023-09-04 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 500 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 3/282616 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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