ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2949G>C (p.Glu983Asp)

gnomAD frequency: 0.00001  dbSNP: rs780485157
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573654 SCV000664985 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-27 criteria provided, single submitter clinical testing The p.E983D variant (also known as c.2949G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 2949. The glutamic acid at codon 983 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was identified in an individual with a personal and/or family history concerning for Lynch syndrome (Pastrello C et al. Genet Med, 2011 Feb;13:115-24). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001350778 SCV001545197 benign Hereditary nonpolyposis colorectal neoplasms 2023-11-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV003470622 SCV004195534 uncertain significance Endometrial carcinoma 2023-09-04 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000573654 SCV004357684 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-28 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with aspartic acid at codon 983 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). 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 1/224028 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 RCV000499422 SCV000592619 uncertain significance Lynch syndrome no assertion criteria provided clinical testing The MSH6 p.Glu983Asp variant was not identified in the literature, nor was it identified in any of the databases searched, including: dbSNP, Exome Variant Server ESP Project, HGMD, UMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, and “MMR Gene Unclassified Variants Database”. Although the p.Glu983 residue is conserved in mammals, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. However, this is not predictive enough to rule out 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 unknown significance.

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