ClinVar Miner

Submissions for variant NM_020975.6(RET):c.785T>C (p.Val262Ala) (rs139790943)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123327 SCV000166634 uncertain significance Multiple endocrine neoplasia, type 2 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 262 of the RET protein (p.Val262Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs139790943, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RET-related disease. ClinVar contains an entry for this variant (Variation ID: 41845). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000034777 SCV000279597 uncertain significance not provided 2016-12-13 criteria provided, single submitter clinical testing This variant is denoted RET c.785T>C at the cDNA level, p.Val262Ala (V262A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). This variant was observed in an individual with a prolactinoma, but was absent in a relative with acromegaly, indicating lack of segregation with a pituitary-related phenotype (Heliövaara 2011). RET Val262Ala was also observed in 1/439 individuals with atherosclerosis, with no specific information about cancer history, as well as in an individual with Hirschprung's disease (Johnson 2012, Fitze 2002). This variant was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. RET Val262Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the Cadherin domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether RET Val262Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000223157 SCV000540171 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 is present in HGMD in 4 papers, with comments suggesting VUS. It has been seen in unaffected patients, as well as one with Hirschprung's disease and an individual with pituitary adenomas but did not segregate in this family. This variant has a Max MAF of 0.032% in ExAC. It is classified with 2 stars as VUS by GeneDx, Invitae, Biesecker, and CSER_CC_NCGL.
Ambry Genetics RCV000573525 SCV000664464 likely benign Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Other data supporting benign classification
Counsyl RCV000663296 SCV000786544 likely benign Multiple endocrine neoplasia, type 2a 2018-05-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034777 SCV000807060 uncertain significance not provided 2015-12-11 criteria provided, single submitter clinical testing
GeneKor MSA RCV000573525 SCV000822200 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000663296 SCV000838371 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000663296 SCV000891636 uncertain significance Multiple endocrine neoplasia, type 2a 2017-12-30 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034777 SCV000043470 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148775 SCV000190512 uncertain significance Hirschsprung disease 2014-06-01 no assertion criteria provided research
Gharavi Laboratory,Columbia University RCV000034777 SCV000920669 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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