ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4001+2TAAC[2] (rs267608132)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074968 SCV000108184 likely benign Lynch syndrome 2019-06-21 reviewed by expert panel curation No effect on splicing in minigene & RT-PCR assay
Ambry Genetics RCV000160732 SCV000187066 uncertain significance Hereditary cancer-predisposing syndrome 2013-08-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000160732 SCV000211368 benign Hereditary cancer-predisposing syndrome 2014-08-19 criteria provided, single submitter clinical testing The variant is found in HEREDICANCER,COLO-HEREDIC panel(s).
Invitae RCV000524200 SCV000262471 benign Hereditary nonpolyposis colon cancer 2018-01-22 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000202155 SCV000339455 benign not specified 2016-02-04 criteria provided, single submitter clinical testing
Counsyl RCV000412187 SCV000489228 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-09-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000202155 SCV000595844 uncertain significance not specified 2017-02-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202155 SCV000601598 likely benign not specified 2016-12-20 criteria provided, single submitter clinical testing
Color RCV000160732 SCV000690428 likely benign Hereditary cancer-predisposing syndrome 2015-02-13 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656542 SCV000805901 likely benign not provided 2017-08-11 criteria provided, single submitter clinical testing
Mendelics RCV000074968 SCV000837929 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202155 SCV000919767 benign not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.4001+12_4001+15delACTA variant results in 4 intronic nucleotides deletion, with 5/5 computational tools predicting 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 0.0012 in 270798 control chromosomes (gnomAD). The observed variant frequency is approximately 8.7 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 benign. The variant, c.4001+12_4001+15delACTA, has been reported in the literature in individuals affected with Lynch Syndrome but also in unaffected controls and was classified as a polymorphism (Peterlongo_2003, Naruse_2009). In addition, the variant was detected in a patient with the pathogenic MSH2 variant c.211+1G>C that was shown to cause aberrant splicing (Naruse_2009). Since the penetrance of Lynch Syndrome (0.67) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and the majority classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000656542 SCV000257294 likely benign not provided 2017-11-10 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000412187 SCV000745655 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-04-29 no assertion criteria provided clinical testing
True Health Diagnostics RCV000160732 SCV000788055 likely benign Hereditary cancer-predisposing syndrome 2017-08-11 no assertion criteria provided clinical testing

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