Submissions for variant NM_000179.3(MSH6):c.1915G>A (p.Glu639Lys)

gnomAD frequency: 0.00003  dbSNP: rs143517321

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164891	SCV000215577	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	The p.E639K variant (also known as c.1915G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1915. The glutamic acid at codon 639 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in an individual with sigmoid colon cancer at age 47 years whose tumor was determined to be MSH6-proficient via immunohistochemistry (Pearlman et al. JAMA Oncol 2017 Apr;3(4):464-471). This alteration has also been reported in patients with colorectal cancer and low grade glioma (Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Shirts BH et al. Genet Med, 2016 10;18:974-81). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000524126	SCV000254285	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000200231	SCV000266204	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094683	SCV000430966	uncertain significance	Lynch syndrome 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000480270	SCV000566008	uncertain significance	not provided	2023-03-07	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; Observed in individuals with glioma, breast cancer, colorectal cancer, and/or polyps (Lu et al., 2015; Shirts et al., 2016; Pearlman et al., 2017; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26845104, 26689913, 27978560, 23621914, 33471991, 17531815, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000164891	SCV000685239	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 639 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 26845104, 27978560), glioma (PMID: 26689913) and breast cancer (PMID: 33471991). This variant has been identified in 4/282398 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.
PreventionGenetics, part of Exact Sciences	RCV004528912	SCV000805852	uncertain significance	MSH6-related disorder	2023-07-05	criteria provided, single submitter	clinical testing	The MSH6 c.1915G>A variant is predicted to result in the amino acid substitution p.Glu639Lys. This variant has been reported in individuals with colorectal cancer, sequenced as part of large cohort screens; however, causation was not established in these studies (see for example, Shirts et al. 2016. PubMed ID: 26845104; Pearlman et al. 2017. PubMed ID: 27978560). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48027037-G-A), and it is classified as uncertain (9) and likely benign (1) in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185463/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480270	SCV000889468	uncertain significance	not provided	2018-08-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781602	SCV000919774	uncertain significance	not specified	2018-11-13	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1915G>A (p.Glu639Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 276788 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1915G>A has been reported in the literature in individuals affected with colon cancer and glioma. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000164891	SCV002535681	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-20	criteria provided, single submitter	curation
Baylor Genetics	RCV003462152	SCV004195552	uncertain significance	Endometrial carcinoma	2023-08-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000200231	SCV004835567	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 639 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 26845104, 27978560), glioma (PMID: 26689913) and breast cancer (PMID: 33471991). This variant has been identified in 4/282398 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.