Submissions for variant NM_000179.3(MSH6):c.3974A>T (p.Lys1325Met)

dbSNP: rs876658189

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215262	SCV000273567	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	The p.K1325M variant (also known as c.3974A>T), located in coding exon 9 of the MSH6 gene, results from an A to T substitution at nucleotide position 3974. The lysine at codon 1325 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well 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.
Color Diagnostics, LLC DBA Color Health	RCV000215262	SCV000537550	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with methionine at codon 1325 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 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.
GeneDx	RCV000485930	SCV000566508	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12019211, 21120944, 17531815)
Invitae	RCV000697066	SCV000825656	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1325 of the MSH6 protein (p.Lys1325Met). 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: 230130). 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.
Baylor Genetics	RCV003462423	SCV004195590	uncertain significance	Endometrial carcinoma	2023-08-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997805	SCV004835180	uncertain significance	Lynch syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with methionine at codon 1325 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 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.