ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1746T>G (p.Phe582Leu) (rs201518545)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235184 SCV000149291 uncertain significance not provided 2020-02-13 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23621914)
Ambry Genetics RCV000115382 SCV000216925 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-11 criteria provided, single submitter clinical testing The p.F582L variant (also known as c.1746T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 1746. The phenylalanine at codon 582 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other 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.
Invitae RCV000230963 SCV000283726 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 582 of the MSH6 protein (p.Phe582Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs201518545, ExAC 0.02%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127563). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. In addition, the leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Counsyl RCV000409045 SCV000487946 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115382 SCV000903501 likely benign Hereditary cancer-predisposing syndrome 2016-09-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192457 SCV001360593 uncertain significance not specified 2019-01-07 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1746T>G (p.Phe582Leu) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245994 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1746T>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235184 SCV001469815 uncertain significance not provided 2020-09-02 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000235184 SCV001713985 uncertain significance not provided 2019-06-07 criteria provided, single submitter clinical testing

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