Submissions for variant NM_000179.3(MSH6):c.2653A>G (p.Lys885Glu)

gnomAD frequency: 0.00001  dbSNP: rs587782593

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000529411	SCV000624782	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-04	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. 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. ClinVar contains an entry for this variant (Variation ID: 455213). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 885 of the MSH6 protein (p.Lys885Glu).
Color Diagnostics, LLC DBA Color Health	RCV000581939	SCV000690284	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 885 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000818	SCV001157883	uncertain significance	not specified	2018-09-20	criteria provided, single submitter	clinical testing	The MSH6 c.2653A>G; p.Lys885Glu variant, to our knowledge, is not reported in the medical literature but is reported as uncertain significance in ClinVar (Variation ID: 455213). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The lysine at codon 885 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Lys885Glu variant is uncertain at this time.
Ambry Genetics	RCV000581939	SCV001177145	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-08	criteria provided, single submitter	clinical testing	The p.K885E variant (also known as c.2653A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2653. The lysine at codon 885 is replaced by glutamic acid, an amino acid with similar properties. In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Mendelics	RCV001000818	SCV002518279	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459169	SCV004195787	uncertain significance	Endometrial carcinoma	2023-05-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003681	SCV004838404	uncertain significance	Lynch syndrome	2023-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 885 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
CeGaT Center for Human Genetics Tuebingen	RCV004546513	SCV005041183	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MSH6: BP4