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

gnomAD frequency: 0.00018  dbSNP: rs201553718

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123299	SCV000166606	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 511 of the RET protein (p.Glu511Lys). This variant is present in population databases (rs201553718, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 20103606, 21551259). ClinVar contains an entry for this variant (Variation ID: 24883). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects RET function (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, Mass General Brigham 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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Mendelics	RCV000411825	SCV000838385	uncertain significance	Multiple endocrine neoplasia type 2A	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
CeGaT Center for Human Genetics Tuebingen	RCV001310920	SCV001500903	uncertain significance	not provided	2020-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001310920	SCV001874040	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate moderate increases in phosphorylation and transforming activity (Muzza et al., 2010; Prazeres et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with medullary thyroid cancer as well as other cancer types (Prazeres et al., 2011; Muzza et al., 2010; Lebeault et al., 2017; Yehia et al., 2018; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 24055113, 21834681, 24336963, 20103606, 21551259, 25637381, 21479187, 26332594, 17316110, 27807062, 28946813, 30758123, 34426522, 14633923, 30446652, 16712668, 29684080, 35264596)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000411825	SCV002526005	uncertain significance	Multiple endocrine neoplasia type 2A	2022-05-31	criteria provided, single submitter	clinical testing	The RET c.1531G>A (p.Glu511Lys) missense change has a maximum subpopulation frequency of 0.031% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in two individuals with medullary thyroid cancer (MTC) with no known family history of MTC or thyroid tumors (PMID: 20103606, 21551259). The variant was also found in three first-degree relatives of one of the affected individuals and all three individuals displayed normal biochemical parameters (PMID: 21551259). Functional assays have shown increased RET and ERK phosphorylation levels and transforming activity at intermediate levels between those of wild-type and a well-established pathogenic variant (PMID: 20103606, 21551259). In summary, the evidence currently available is insufficient to determine the role of this variant in multiple endocrine neoplasia. It has therefore been classified as of uncertain significance.
Sema4, Sema4	RCV000561335	SCV002529933	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000411825	SCV002761452	uncertain significance	Multiple endocrine neoplasia type 2A	2020-04-23	criteria provided, single submitter	clinical testing	PM2, PS3, BS4
Myriad Genetics, Inc.	RCV000411825	SCV004018078	likely benign	Multiple endocrine neoplasia type 2A	2024-05-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001310920	SCV004225224	uncertain significance	not provided	2022-08-03	criteria provided, single submitter	clinical testing	BS1
CSER _CC_NCGL, University of Washington	RCV000148777	SCV000190514	uncertain significance	Medullary thyroid carcinoma	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004532394	SCV004119862	uncertain significance	RET-related disorder	2023-11-27	no assertion criteria provided	clinical testing	The RET c.1531G>A variant is predicted to result in the amino acid substitution p.Glu511Lys. This variant has been identified in individuals with medullary thyroid cancer, but was also found in unaffected family members (Muzza et al. 2010. PubMed ID: 20103606; Prazeres et al. 2011. PubMed ID: 21551259). In vitro analysis showed that this variant resulted in increased transforming potential of NIH3T3 fibroblasts, and using a phosphospecific antibody, western blot showed that this variant more readily induced phosphorylation compared to wild type (Prazeres et al. 2011. PubMed ID: 21551259). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/24883/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.