Submissions for variant NM_000179.3(MSH6):c.1130A>C (p.Lys377Thr)

dbSNP: rs550221570

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629781	SCV000750737	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-01-27	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH6-related disease. This variant is present in population databases (rs550221570, ExAC 0.01%). This sequence change replaces lysine with threonine at codon 377 of the MSH6 protein (p.Lys377Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine.
Ambry Genetics	RCV002325197	SCV002610443	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-13	criteria provided, single submitter	clinical testing	The p.K377T variant (also known as c.1130A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 1130. The lysine at codon 377 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002510939	SCV002820441	uncertain significance	not provided	2022-07-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)
All of Us Research Program, National Institutes of Health	RCV004002774	SCV004836187	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 377 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 1/250966 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.