ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3852G>A (p.Thr1284=) (rs2229018)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165384 SCV000216111 likely benign Hereditary cancer-predisposing syndrome 2014-11-11 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000524192 SCV000261299 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000418187 SCV000513704 benign not specified 2015-08-27 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.
Color Health, Inc RCV000165384 SCV000690415 likely benign Hereditary cancer-predisposing syndrome 2016-11-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000418187 SCV000695895 likely benign not specified 2019-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000663078 SCV000786155 likely benign Hereditary nonpolyposis colorectal cancer type 5 2018-03-12 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356238 SCV001551353 likely benign not provided no assertion criteria provided clinical testing The MSH6 p.Thr1284= variant was identified in 1 of 178 proband chromosomes (frequency: 0.006) from Dutch individuals or families with suspected HNPCC carrying MSI-H + MSH6 IHC deficient tumours or non-MSI-H tumours, the affected case having a non-MSI-H tumour (Kets 2006). The variant was also identified in dbSNP (ID: rs2229018) “With Uncertain significance,other allele”, ClinVar (uncertain significance, reviewed by an expert panel (last evaluated 2013); submitters: benign by GeneDx, likely benign by Ambry Genetics and Invitae, uncertain significance by InSIGHT), Cosmic (2x in a chondrosarcoma and endometrial carcinoma), Insight Colon Cancer Gene Variant Database (1X as Class 3), Mismatch Repair Genes Variant Database (1x), but was not identified in GeneInsight-COGR, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database. The variant was identified in control databases in 16 of 276758 chromosomes at a frequency of 0.00006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr1284= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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