ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.4001+4_4001+8dup (rs587782853)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132454 SCV000187548 likely benign Hereditary cancer-predisposing syndrome 2019-10-01 criteria provided, single submitter clinical testing In silico models in agreement (benign);RNA Studies
GeneDx RCV000132454 SCV000211367 benign Hereditary cancer-predisposing syndrome 2014-09-17 criteria provided, single submitter clinical testing The variant is found in BR-OV-HEREDIC panel(s).
Invitae RCV001080987 SCV000253115 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000409890 SCV000489495 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-10-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000196451 SCV000601599 likely benign not provided 2020-04-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132454 SCV000902893 likely benign Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing
Mendelics RCV000409890 SCV001135860 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000196451 SCV000592667 uncertain significance not provided no assertion criteria provided clinical testing The MSH6 c.4001+4_4001+8dup variant was identified in 1 of 256 proband chromosomes (frequency: 0.004) from individuals or families with hereditary cancer (Watson 2013). The variant was also identified in dbSNP (ID: rs781320845) as “other”, Clinvitae database (conflicting interpretations of pathogenicity), ClinVar database (as uncertain significance by Ambry Genetics, likely benign by Invitae, benign by GeneDx) and UMD (1x with an “unclassified variant” classification). The variant was not identified in GeneInsight - COGR database, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database” . The variant was identified in the Exome Aggregation Consortium database (August 8, 2016) in 4 of 111884 chromosomes (freq. 3.58x10-5) in the following populations: European (Non-Finnish) in 4 of 61054 but was not seen in African, East Asian, Finnish, Latino, Other or South Asian populations. In addition this variant was identified in case in our laboratory as co-occurring with a pathogenic MLH1 p.Lys751SerfsX3 variant, increasing the likelihood that it does not have clinical significance. The c.4001+4_4001+8dup variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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. This variant is classified as a variant of uncertain significance.

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