Submissions for variant NM_000179.3(MSH6):c.3841G>C (p.Glu1281Gln)

gnomAD frequency: 0.00001  dbSNP: rs876659115

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216678	SCV000275193	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.E1281Q variant (also known as c.3841G>C), located in coding exon 9 of the MSH6 gene, results from a G to C substitution at nucleotide position 3841. The glutamic acid at codon 1281 is replaced by glutamine, an amino acid with highly similar properties. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Color Diagnostics, LLC DBA Color Health	RCV000216678	SCV000685451	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1281 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 hereditary cancer in the literature. This variant has been identified in 1/250892 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.
Invitae	RCV000704640	SCV000833596	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000708893	SCV000837922	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001358640	SCV004034710	uncertain significance	not provided	2023-09-05	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; Observed in an unaffected individual with a family history of breast and/or ovarian cancer (Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 17531815, 21120944, 32885271)
Baylor Genetics	RCV003469028	SCV004195607	uncertain significance	Endometrial carcinoma	2023-08-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708893	SCV004835151	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1281 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 hereditary cancer in the literature. This variant has been identified in 1/250892 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358640	SCV001554434	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Glu1281Gln variant was not identified in the literature nor was it identified in the COGR, COSMIC, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs876659115) as “With Uncertain significance allele”, and in the ClinVar and Clinvitae databases (classified as uncertain significance by Ambry Genetics and Color Genomics). The variant was identified in control databases in 1 of 245856 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the Latino population in 1 of 33540 chromosomes (freq: 0.00003), but not in the African, Other, European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu1281 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.