Submissions for variant NM_000179.3(MSH6):c.3803C>T (p.Ala1268Val)

dbSNP: rs587779293

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461283	SCV000551128	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-05-05	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 410447). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1268 of the MSH6 protein (p.Ala1268Val).
GeneDx	RCV000481062	SCV000569180	uncertain significance	not provided	2016-05-05	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3803C>T at the cDNA level, p.Ala1268Val (A1268V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala1268Val 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 Ala1268Val occurs at a position that is conserved across species and is located within the MutS V domain (Terui 2013). Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function, while splicing-based models predict that this variant may result in the creation of a cryptic donor site and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH6 Ala1268Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000663066	SCV000786131	uncertain significance	Lynch syndrome 5	2018-03-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356690	SCV002622795	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-05	criteria provided, single submitter	clinical testing	The p.A1268V variant (also known as c.3803C>T), located in coding exon 9 of the MSH6 gene, results from a C to T substitution at nucleotide position 3803. The alanine at codon 1268 is replaced by valine, an amino acid with similar properties. This amino acid position is highly 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.
Myriad Genetics, Inc.	RCV000663066	SCV004018862	uncertain significance	Lynch syndrome 5	2023-03-27	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Color Diagnostics, LLC DBA Color Health	RCV002356690	SCV004357761	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1268 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 1/251016 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	RCV004001831	SCV004818113	uncertain significance	Lynch syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1268 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 1/251016 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.