ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs369042519
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Total submissions: 7
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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 2024-06-05 criteria provided, single submitter clinical testing The c.3191C>T (p.A1064V) alteration is located in exon 5 (coding exon 5) of the MSH6 gene. This alteration results from a C to T substitution at nucleotide position 3191, causing the alanine (A) at amino acid position 1064 to be replaced by a valine (V). Based on insufficient or conflicting evidence, 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.
Labcorp Genetics (formerly Invitae), Labcorp 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.
Baylor Genetics RCV004567003 SCV005054936 uncertain significance Endometrial carcinoma 2024-02-07 criteria provided, single submitter clinical testing

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