Submissions for variant NM_000179.3(MSH6):c.1189T>C (p.Tyr397His)

dbSNP: rs587779913

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212648	SCV000149280	uncertain significance	not provided	2015-08-18	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1189T>C at the cDNA level, p.Tyr397His (Y397H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in a gastric adenocarcinoma (COSMIC). MSH6 Tyr397His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Tyr397His occurs at a position that is not conserved and is located within the MutS domain I and MSH2 binding site (Kariola 2002, Terui 2013). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on the currently available information, we consider MSH6 Tyr397His to be a variant of uncertain significance.
Ambry Genetics	RCV000115371	SCV000186264	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	The p.Y397H variant (also known as c.1189T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1189. The tyrosine at codon 397 is replaced by histidine, 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.
Invitae	RCV000457819	SCV000551082	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 397 of the MSH6 protein (p.Tyr397His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 127557). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000115371	SCV000911826	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 397 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.
Baylor Genetics	RCV003467039	SCV004195786	uncertain significance	Endometrial carcinoma	2023-05-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997233	SCV004843114	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 397 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.