ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1493A>G (p.Lys498Arg)

gnomAD frequency: 0.00002  dbSNP: rs147136417
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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 RCV001011856 SCV001172230 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-11 criteria provided, single submitter clinical testing The p.K498R variant (also known as c.1493A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1493. The lysine at codon 498 is replaced by arginine, an amino acid with highly similar properties. This variant was 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 not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Invitae RCV001215217 SCV001386947 benign Hereditary nonpolyposis colorectal neoplasms 2023-09-13 criteria provided, single submitter clinical testing
GeneDx RCV002279707 SCV002567369 uncertain significance not provided 2022-08-03 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: 23621914, 17531815, 21120944)
All of Us Research Program, National Institutes of Health RCV004004504 SCV004839306 uncertain significance Lynch syndrome 2023-09-17 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 498 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 hereditary cancer in the literature. This variant has been identified in 5/282664 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 RCV001354837 SCV001549548 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Lys498Arg variant was not identified in the literature nor was it identified in the ClinVar, or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs147136417). The variant was identified in control databases in 4 of 276986 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 4 of 24030 chromosomes (freq: 0.0002), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys498 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.

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