ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.4002-10T>A (rs545466048)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081736 SCV000166235 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000590285 SCV000211331 likely benign not provided 2019-04-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30306255, 25561518, 26181448, 21056691)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000160702 SCV000539708 uncertain significance not specified 2016-06-16 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: 1 paper in HGMD describes as VUS; ClinVar: 1LB; Unlikely to impact splicing
Genetic Services Laboratory, University of Chicago RCV000160702 SCV000595857 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590285 SCV000601600 likely benign not provided 2019-10-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160702 SCV000695909 benign not specified 2019-05-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.4002-10T>A alters a non-conserved nucleotide. 4/5 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 0.00026 in 244976 control chromosomes (gnomAD). The observed variant frequency is approximately 1.8 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 benign. The variant, c.4002-10T>A, has been reported in the literature in colorectal, gastric or breast cancer patients without strong evidence for causality (Limburg_2011, Yamashita_2013, Bonache_2018). A co-occurrence with another pathogenic variant has been reported (MSH6 c.3477C>G, p.Tyr1159X; internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS (n=5), Likely benign (n=1), Benign (n=1)) and one expert panel, InSiGHT, classified as uncertain significance before 2014. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000074975 SCV000837933 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771079 SCV000902614 likely benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Mendelics RCV000986753 SCV001135868 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590285 SCV001152304 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986753 SCV001300825 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-04-18 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357666 SCV001553196 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6, c.4002-10T>A, r.(spl?) variant was identified in 31 of 48 proband chromosomes (frequency: 0.6) from individuals or families with familial colorectal cancer (Lucci-Cordisco 2001). The variant was also identified in dbSNP (ID: rs545466048) as “With Uncertain significance allele”, ClinVar (1x likely benign: Invitae; 3x uncertain significance: InSiGHT, GeneDx, Partners HealthCare), COSMIC (1x confirmed somatic in Wilms tumour of kidney), UMD-LSDB (biological significance neutral; variation in splice site consensus value <10%), Insight Colon Cancer Gene Variant Database (3x uncertain significance), Mismatch Repair Genes Variant Database (as c.4002-8dupA polymorphism in Verma 1999 and Lucci-Cordisco 2001, describing this as a poly A expansion where “sequencing suggests that different length variants exist or are highly prone to stuttering so that it is not possible to sequence across them"), Insight Hereditary Tumors Database (3x effect unknown), databases. The variant was not identified in MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 57 of 213460 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). 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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