ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1526T>C (p.Val509Ala) (rs63751005)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
GeneDx RCV000034492 SCV000149285 benign not provided 2018-11-29 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24055113, 25637381, 15184898, 24978188, 16341805, 22703879, 22949387, 23621914, 20176959, 16237223, 27153395, 25985138, 28531214, 14520694)
Invitae RCV001079926 SCV000166211 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115376 SCV000184181 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Pathway Genomics RCV000172817 SCV000223783 likely benign Lynch syndrome I 2014-10-30 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
Color Health, Inc RCV000115376 SCV000537406 likely benign Hereditary cancer-predisposing syndrome 2014-12-18 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000178051 SCV000601509 likely benign not specified 2017-03-18 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659890 SCV000781787 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034492 SCV000888243 benign not provided 2018-04-07 criteria provided, single submitter clinical testing
Mendelics RCV000659890 SCV001135807 benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000659890 SCV001299859 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034492 SCV001502308 likely benign not provided 2021-02-01 criteria provided, single submitter clinical testing
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 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000178051 SCV000257214 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354372 SCV001548974 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Val509Ala variant was identified in 4 of 344 proband chromosomes (frequency: 0.01) from individuals or families with hereditary non-polyposis colon cancer and was present in 4 of 1512 control chromosomes (frequency: 0.003) from healthy individuals (Dovrat 2005, Hedge 2005, Peterlongo 2003, Johnston 2012). The variant was also identified in dbSNP (rs63751005) as “with other allele”, ClinVar (classified as likely benign by InSiGHT expert panel in 2013, Color, Eurofins and 4 other submitters; as benign by Invitae, GeneDx, Ambry Genetics and 1 other submitter; and as uncertain significance by Mayo Clinic and 3 other submitters) and UMD-LSDB (observed 5x). The variant was identified in control databases in 278 of 282,624 chromosomes (3 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 244 of 10,364 chromosomes (freq: 0.02), Other in 13 of 7218 chromosomes (freq: 0.002), and European in 21 of 129,016 chromosomes (freq: 0.0002), while it was not observed in the African, Latino, East Asian, Finnish or South Asian populations. The variant had no observed effect on MMR activity in mouse embryonic stem cells (Houlleberghs 2017). The p.Val509 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000178051 SCV001808421 benign not specified no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000034492 SCV001921261 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000034492 SCV001959706 likely benign not provided no assertion criteria provided clinical testing

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