ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.33C>G (p.Phe11Leu) (rs747802641)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166008 SCV000216767 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing The p.F11L variant (also known as c.33C>G), located in coding exon 1 of the MSH6 gene, results from a C to G substitution at nucleotide position 33. The phenylalanine at codon 11 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly 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.
GeneDx RCV000679237 SCV000279089 uncertain significance not provided 2020-11-30 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22949387)
Invitae RCV001085290 SCV000624857 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166008 SCV000690350 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679237 SCV000805888 uncertain significance not provided 2017-11-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264551 SCV001442759 likely benign not specified 2020-10-09 criteria provided, single submitter clinical testing Variant summary: MSH6 c.33C>G (p.Phe11Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 245118 control chromosomes, predominantly at a frequency of 0.001 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.33C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=1) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign.

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