Submissions for variant NM_000179.3(MSH6):c.247G>A (p.Ala83Thr)

dbSNP: rs755964436

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000822716	SCV000963530	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-07	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 664593). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 83 of the MSH6 protein (p.Ala83Thr).
Ambry Genetics	RCV001015640	SCV001176495	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	The p.A83T variant (also known as c.247G>A), located in coding exon 1 of the MSH6 gene, results from a G to A substitution at nucleotide position 247. The alanine at codon 83 is replaced by threonine, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469301	SCV002765952	uncertain significance	not specified	2022-11-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002845	SCV004832000	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 83 of 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 not been identified 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.