ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.178T>C (p.Leu60=) (rs35819209)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080064 SCV000166214 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000212625 SCV000170366 benign not specified 2014-03-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000126838 SCV000214176 likely benign Hereditary cancer-predisposing syndrome 2015-01-06 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000412370 SCV000488979 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-07-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000126838 SCV000537511 likely benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212625 SCV000601516 likely benign not specified 2017-02-08 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679218 SCV000805849 likely benign not provided 2017-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679218 SCV000889459 likely benign not provided 2018-05-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212625 SCV001362734 likely benign not specified 2019-03-01 criteria provided, single submitter clinical testing Variant summary: MSH6 c.178T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.4e-05 in 157094 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (6.4e-05 vs 0.00014), allowing no conclusion about variant significance. c.178T>C has been reported in the literature in individuals affected with colon cancer. This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356200 SCV001551304 likely benign Lynch syndrome no assertion criteria provided clinical testing The MSH6 p.Leu60= variant was identified in 1 of 2132 proband chromosomes (frequency: 0.00046) from individuals or families with colorectal cancer (Hampel 2005). The variant was also identified in the following databases: dbSNP (ID: rs35819209) as “With Likely benign allele”, ClinVar and Clinvitae (6x as benign by Invitae and GeneDx, and as likely benign by Ambry Genetics, Counsyl, Color Genomics and Quest diagnostics), Insight Colon Cancer Gene Variant Database (1x) and Insight Hereditary Tumors Database (2x). The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 10 of 157094 chromosomes at a frequency of 0.000064 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish in 9 of 66828 chromosomes (freq: 0.00013) and Ashkenazi Jewish in 1 of 6288 chromosomes (freq: 0.00016); it was not observed in the African, “Other”, Latino, East Asian, European Finnish or South Asian populations. The p.Leu60Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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