ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1531G>A (p.Glu511Lys) (rs201553718)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123299 SCV000166606 uncertain significance Multiple endocrine neoplasia, type 2 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 511 of the RET protein (p.Glu511Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs201553718, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with medullary thyroid carcinoma (PMID: 20103606, 21551259). Currently there is insufficient evidence to conclude whether this variant segregates with disease (PMID: 21551259). ClinVar contains an entry for this variant (Variation ID: 24883). Experimental studies have shown that this variant moderately increases RET kinase activity and transforming potential relative to the wild-type protein when expressed in cell culture (PMID: 20103606, 21551259). 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.
Counsyl RCV000410289 SCV000489739 uncertain significance Multiple endocrine neoplasia, type 2b 2015-11-21 criteria provided, single submitter clinical testing
Counsyl RCV000411825 SCV000489740 uncertain significance Multiple endocrine neoplasia, type 2a 2015-11-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000454639 SCV000540174 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 6 papers with comments suggesting VUS and benign. It was seen in a proband with medullary thyroid carcinoma but was found in unaffected relatives. It is present in ExAC with a Max MAF of 0.03% (35/114960 European chrs). It is classified in ClinVar with 1 star as VUS by Invitae, CSER_CC_NCGL, and ARUP. 14 non-mammals have a Lys at this position.
Ambry Genetics RCV000561335 SCV000674743 likely benign Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Mendelics RCV000411825 SCV000838385 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000454639 SCV001372252 likely benign not specified 2020-06-16 criteria provided, single submitter clinical testing Variant summary: RET c.1531G>A (p.Glu511Lys) results in a conservative amino acid change located in the extracellular domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 226932 control chromosomes. The observed variant frequency is approximately 4.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is benign. c.1531G>A has been reported in the literature in affected and unaffected individuals from a family with apparently sporadic MTC (AS-MTC) (Prazeres_2006 and 2011). Due to non-conclusive co-segregation, these reports do not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. At least two publications report in-vitro experimental evidence evaluating an impact on protein function. Both demonstrated increased RET and ERK phosphorylation levels and transforming activity at intermediate levels between wild-type and the well known p.Cys634Arg positive control (Muzza_2010, Prazeres_2011). However, these findings do not allow convincing conclusions about the variant effect in-vivo. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign for Multiple Endocrine Neoplasia Type 2.
Research and Development, ARUP Laboratories RCV000454639 SCV000042430 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only First report, single French individual: MTC only (66 yr). Second report, single Portuguese family, 4 have the variant genotype: 1 MTC (65 yr), 3 asymptomatic (49, 51, and 56 yr). Two unrelated French individual reports: 38 yr and 73 yr with MTC (PMID 28946813). In vitro studies: PMID 21551259. Present in GnomAD at 0.016%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731).
CSER _CC_NCGL, University of Washington RCV000148777 SCV000190514 uncertain significance Medullary thyroid carcinoma 2014-06-01 no assertion criteria provided research

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