Submissions for variant NM_000179.3(MSH6):c.3191C>T (p.Ala1064Val)

gnomAD frequency: 0.00006  dbSNP: rs369042519

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759861	SCV000149314	uncertain significance	not provided	2015-11-24	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3191C>T at the cDNA level, p.Ala1064Val (A1064V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala1064Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ala1064Val occurs at a position that is not conserved across species and is located in MutS domain III (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function (Terui 2013). Based on currently available evidence, it is unclear whether MSH6 Ala1064Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000216009	SCV000277148	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	The p.A1064V variant (also known as c.3191C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3191. The alanine at codon 1064 is replaced by valine, an amino acid with similar 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.
Color Diagnostics, LLC DBA Color Health	RCV000216009	SCV000690326	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1064 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 hereditary cancer in the literature. This variant has been identified in 5/282752 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.
Invitae	RCV000691203	SCV000818951	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759861	SCV000889486	uncertain significance	not provided	2017-09-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997246	SCV004837246	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1064 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 5/282752 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.