ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1946C>T (p.Ser649Leu) (rs148935214)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163375 SCV000213915 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148770 SCV000190507 likely benign Elevated basal serum calcitonin 2014-06-01 no assertion criteria provided research
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224141 SCV000281200 benign not provided 2016-05-06 criteria provided, single submitter clinical testing
Counsyl RCV000663272 SCV000786504 likely benign Multiple endocrine neoplasia, type 2a 2018-05-16 criteria provided, single submitter clinical testing
GeneDx RCV000121978 SCV000514408 likely benign not specified 2016-01-26 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.
GeneKor MSA RCV000163375 SCV000822193 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000121978 SCV000086187 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000123304 SCV000166611 likely benign Multiple endocrine neoplasia, type 2 2017-12-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000121978 SCV000540172 uncertain significance not specified 2017-01-24 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 DM in HGMD related to elevated basal serum calcitonin. It has been reported in 12 papers, with 2 related to Hirschprung disease. The comments suggest that it is not pathogenic. This variant is present at 0.05% in ExAC. It is classified in ClinVar with 1 star as Likely benign/Benign by Invitae and Children's Mercy Hospital, and as VUS by Ambry and ARUP. Variant occurs at greater frequency in population than expected for disorder
Mendelics RCV000663272 SCV000838393 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000224141 SCV000807017 likely benign not provided 2017-05-04 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000121978 SCV000055379 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only PMID 19906784 and 29656518 indicates p.S649L is a rare non-pathogenic polymorphism rather than a disease-causing mutation. GnomAD frequency 0.033%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731). If mutation, p.S649L may have low or variable penetrance. Four individual reports: 2 MTC only, 1 HPT only (24 yr), 1 elevated calcitonin (47 yr). First family report, 5 have the variant genotype: 1 MTC only (69 yr). Second family report, 3 have the variant genotype: 2 asymptomatic (75, 41 yr), 1 elevated calcitonin (43 yr). In vitro studies (PMID 18322301). Additional references: PMID 15320968, 21551259, and MEN2 meeting poster P20 http://www.hormones.gr/preview.php?c_id=622. Has been found with other RET changes, see c.[1900T>C];[1946C>T], c.[1902C>G];[1946C>T] and c.1946C>T(;)2372A>T.

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