Submissions for variant NM_000179.3(MSH6):c.3977T>C (p.Met1326Thr)

dbSNP: rs757089977

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480936	SCV000567411	uncertain significance	not provided	2015-07-23	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3977T>C at the cDNA level, p.Met1326Thr (M1326T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Met1326Thr 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. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Met1326Thr occurs at a position that is not conserved and is located in the MutS domain V (Terui 2013). A published in silico algorithm predicted this variant to be of uncertain significance, and in house in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function (Terui 2013). Based on currently available information, it is unclear whether MSH6 Met1326Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574295	SCV000669986	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-18	criteria provided, single submitter	clinical testing	The p.M1326T variant (also known as c.3977T>C), located in coding exon 9 of the MSH6 gene, results from a T to C substitution at nucleotide position 3977. The methionine at codon 1326 is replaced by threonine, an amino acid with 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001348367	SCV001542667	benign	Hereditary nonpolyposis colorectal neoplasms	2023-08-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002305	SCV004821998	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480936	SCV005623503	uncertain significance	not provided	2024-08-12	criteria provided, single submitter	clinical testing	The MSH6 c.3977T>C (p.Met1326Thr) variant has not been reported in individuals with MSH6-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/247110 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.