ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1526T>C (p.Val509Ala) (rs63751005)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000034492 SCV000885718 likely benign not provided 2018-05-06 criteria provided, single submitter clinical testing The MSH6 c.1526T>C; p.Val509Ala variant (rs63751005) is reported in the literature in individuals with lynch syndrome (Hegde 2005, Lipkin 2004), but is also found in the general population with an overall allele frequency of 0.1% (268/276940 alleles, including 2 homozygotes) in the Genome Aggregation Database, with an increased frequency of 2.3% in the Askenazi Jewish population. Functional analyses do not show a significant impact on protein function (Houlleberghs 2017, Martinez 2010). This variant is reported as benign or likely benign by multiple laboratories in ClinVar (Variation ID: 41588). The valine at codon 509 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the high frequency in the general population, this variant is considered to be likely benign. REFERENCES Hegde M et al. Assay validation for identification of hereditary nonpolyposis colon cancer-causing mutations in mismatch repair genes MLH1, MSH2, and MSH6. J Mol Diagn. 2005 Oct;7(4):525-34. Houlleberghs H et al. Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity. PLoS Genet. 2017 May 22;13(5):e1006765. Lipkin SM et al. The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nat Genet. 2004 Jul;36(7):694-9. Martinez SL et al. Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5070-5.
Ambry Genetics RCV000115376 SCV000184181 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034492 SCV000043355 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER_CC_NCGL; University of Washington Medical Center RCV000074661 SCV000190358 likely benign Lynch syndrome 2016-08-15 no assertion criteria provided research Originally interpreted based on literature review PMID: 25637381. Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 63 year male with a history of over 30 colon polyps and a family history of colon cancer.
Center for Human Genetics, Inc RCV000659890 SCV000781787 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000115376 SCV000537406 likely benign Hereditary cancer-predisposing syndrome 2014-12-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000178051 SCV000230037 likely benign not specified 2015-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000178051 SCV000149285 benign not specified 2014-09-03 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.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074661 SCV000107863 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research MAF >1% in a specific population
Invitae RCV000524114 SCV000166211 benign Hereditary nonpolyposis colon cancer 2018-01-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000178051 SCV000539704 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified as Likely benign in ClinVar with 3 stars by InSiGHT (expert panel), Pathway Genomics, Emory, CSER_CC_NCGL, and as Benign by Invitae, GeneDx, Ambry, and as VUS by Mayo and Biesecker lab. It has been seen in 9 papers in HGMD, with the comments mostly suggesting that it is likely benign. It is in gnomAD at a frequency of 2.3% of Ashkenazi Jewish chromosomes.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000178051 SCV000257214 uncertain significance not specified no assertion criteria provided research
Pathway Genomics RCV000172817 SCV000223783 likely benign Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000178051 SCV000601509 likely benign not specified 2017-03-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034492 SCV000888243 benign not provided 2018-04-07 criteria provided, single submitter clinical testing

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