ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2599G>A (p.Val867Ile)

gnomAD frequency: 0.00001  dbSNP: rs745954217
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526734 SCV000624775 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-04-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567854 SCV000662486 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-09 criteria provided, single submitter clinical testing The p.V867I variant (also known as c.2599G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2599. The valine at codon 867 is replaced by isoleucine, an amino acid with highly similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). 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.
Color Diagnostics, LLC DBA Color Health RCV000567854 SCV001344434 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-31 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 867 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 been reported in an individual affected with melanoma (PMID: 29684080). This variant has been identified in 3/249814 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.
All of Us Research Program, National Institutes of Health RCV004003680 SCV004842748 uncertain significance Lynch syndrome 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 867 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 been reported in an individual affected with melanoma (PMID: 29684080). This variant has been identified in 3/249814 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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