Submissions for variant NM_000179.3(MSH6):c.1757T>C (p.Val586Ala)

gnomAD frequency: 0.00001  dbSNP: rs730881792

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160670	SCV000211281	uncertain significance	not provided	2016-06-27	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1757T>C at the cDNA level, p.Val586Ala (V586A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Val586Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. MSH6 Val586Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the MutS domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Val586Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000545304	SCV000624689	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774598	SCV000908380	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-22	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 586 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/31404 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781596	SCV000919766	uncertain significance	not specified	2018-04-23	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1757T>C (p.Val586Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 30972 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1757T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000774598	SCV001173578	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-11	criteria provided, single submitter	clinical testing	The p.V586A variant (also known as c.1757T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1757. The valine at codon 586 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003998493	SCV004840063	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 586 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31404 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.