Submissions for variant NM_000179.3(MSH6):c.2183A>C (p.Lys728Thr)

dbSNP: rs35552856

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657127	SCV000279963	uncertain significance	not provided	2017-06-29	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2183A>C at the cDNA level, p.Lys728Thr (K728T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant was observed in at least one individual with colorectal cancer (Kariola 2004, Hampel 2005). Tumor testing via mismatch repair immunohistochemistry showed loss of the MLH1 protein, but MLH1 promoter hypermethylation was detected. In vitro mismatch repair assays showed mismatch repair activity, heterodimer formation with MSH2, and protein expression similar to wild type (Kariola 2004). MSH6 Lys728Thr was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Lys728Thr occurs at a position that is conserved in mammals and is located within the Lever domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Lys728Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV000221222	SCV000595852	uncertain significance	not specified	2016-11-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563245	SCV000664863	likely benign	Hereditary cancer-predisposing syndrome	2021-05-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000688768	SCV000816392	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000563245	SCV000908393	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 728 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). A functional study has shown that this variant does not impact MSH6 protein expression or mismatch repair activity in vitro (PMID: 15354210). This variant has been reported in an individual affected with colorectal cancer with tumor showing MLH1 promoter methylation and loss of MLH1 protein expression (PMID: 15354210). This variant has been identified in 1/250944 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	RCV003997073	SCV004836140	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 728 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). A functional study has shown that this variant does not impact MSH6 protein expression and function in vitro (PMID: 15354210). This variant has been reported in an individual affected with colorectal cancer with tumor showing MLH1 promoter methylation and loss of MLH1 protein expression (PMID: 15354210). This variant has been identified in 1/250944 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.