Submissions for variant NM_000179.3(MSH6):c.190G>C (p.Ala64Pro)

gnomAD frequency: 0.00002  dbSNP: rs587779921

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759850	SCV000149295	uncertain significance	not provided	2014-02-07	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.190G>C at the cDNA level, p.Ala64Pro (A64P) at the protein level, and results in the change of an Alanine to a Proline (GCG>CCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala64Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The MSH6 Ala64Pro variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The variant occurs at a position that is moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on currently available information, it is unclear whether MSH6 Ala64Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000214011	SCV000274033	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	clinical testing	The p.A64P variant (also known as c.190G>C), located in coding exon 1 of the MSH6 gene, results from a G to C substitution at nucleotide position 190. The alanine at codon 64 is replaced by proline, an amino acid with highly similar properties. 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	RCV000214011	SCV000685238	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	This variant is located in 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/112060 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759850	SCV000889467	uncertain significance	not provided	2018-05-04	criteria provided, single submitter	clinical testing
Invitae	RCV001041141	SCV001204741	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-08-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528799	SCV004108344	uncertain significance	MSH6-related disorder	2023-05-30	criteria provided, single submitter	clinical testing	The MSH6 c.190G>C variant is predicted to result in the amino acid substitution p.Ala64Pro. This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48010562-G-C). In ClinVar, this variant is interpreted as uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127567/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997239	SCV004828514	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This variant is located in 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/112060 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.