ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1746T>G (p.Phe582Leu)

gnomAD frequency: 0.00005  dbSNP: rs201518545
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235184 SCV000149291 uncertain significance not provided 2023-09-11 criteria provided, single submitter clinical testing 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, 37043650)
Ambry Genetics RCV000115382 SCV000216925 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-24 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 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-24 criteria provided, single submitter clinical testing
Counsyl RCV000409045 SCV000487946 uncertain significance Lynch syndrome 5 2015-12-04 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health 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
Genetic Services Laboratory, University of Chicago RCV001192457 SCV002070029 uncertain significance not specified 2020-01-09 criteria provided, single submitter clinical testing DNA sequence analysis of the MSH6 gene demonstrated a sequence change, c.1746T>G, in exon 4 that results in an amino acid change, p.Phe582Leu. This sequence change does not appear to have been previously described in patients with MSH6-related disorders and has been described in the gnomAD database with a frequency of 0.01% in African populations (dbSNP rs201518545). The p.Phe582Leu change affects a moderately conserved amino acid residue located in a domain of the MSH6 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Phe582Leu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Phe582Leu change remains unknown at this time.
Sema4, Sema4 RCV000115382 SCV002535656 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-15 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000409045 SCV004019017 likely benign Lynch syndrome 5 2023-03-29 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Baylor Genetics RCV003460812 SCV004197670 uncertain significance Endometrial carcinoma 2023-10-04 criteria provided, single submitter clinical testing

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