ClinVar Miner

Submissions for variant NM_020975.6(RET):c.874G>A (p.Val292Met) (rs34682185)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565970 SCV000674801 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034779 SCV000043472 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034779 SCV000692679 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034779 SCV000609569 benign not provided 2017-04-12 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000755685 SCV000883098 uncertain significance Multiple endocrine neoplasia, type 2b 2018-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000034779 SCV000616852 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing This variant is denoted RET c.874G>A at the cDNA level, p.Val292Met (V292M) at the protein level, andresults in the change of a Valine to a Methionine (GTG>ATG). This variant was observed in at least one individual withpheochromocytoma and medullary thyroid cancer and four individuals with Hirschsprung disease (Castellone 2010, So2011, Ngo 2012). This variant has also been identified in 1/62 healthy East Asian individuals undergoing wholegenome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus theunaffected status of this individual may not be significant. RET Val292Met was observed at an allele frequency of0.624% (52/8336) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project,The 1000 Genomes Consortium 2015, Lek 2016).Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. RETVal292Met occurs at a position that is conserved across species and is located in the extracellular topological domainand cadherin domain (Garcia-Barcelo 2004). In silico analyses are inconsistent regarding the effect this variant mayhave on protein structure and function. Based on currently available evidence, it is unclear whether RET Val292Met isa pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000121992 SCV000086203 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000354891 SCV000362271 likely benign Renal adysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000276548 SCV000362272 likely benign Pheochromocytoma 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000333869 SCV000362273 likely benign Hirschsprung Disease, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000367517 SCV000362274 likely benign Multiple endocrine neoplasia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000167929 SCV000218577 benign Multiple endocrine neoplasia, type 2 2018-01-04 criteria provided, single submitter clinical testing
Mendelics RCV000021761 SCV000838372 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000034779 SCV000807063 likely benign not provided 2017-05-04 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000021761 SCV000055356 pathogenic Multiple endocrine neoplasia, type 2a 2018-05-04 no assertion criteria provided literature only Family report, one has the mutation genotype: unilateral MTC and unilateral Pheo at 44 yr. Single individual report, p.V292M was found in the germline of a 45 yr old colorectal cancer patient: No mention of MEN2 screening (PMID 17344846). GnomAD frequency 0.055%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731). Has been found with other RET changes: see c.[200G>A;874G>A;2944C>T] and c.[1901G>A];[200G>A;874G>A;2944C>T].

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.