Submissions for variant NM_020975.6(RET):c.1699G>A (p.Asp567Asn)

gnomAD frequency: 0.00014  dbSNP: rs147219360

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081705	SCV000166608	likely benign	Multiple endocrine neoplasia, type 2	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163453	SCV000214000	likely benign	Hereditary cancer-predisposing syndrome	2019-04-13	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455280	SCV000540175	uncertain significance	not specified	2016-03-31	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: Only reported in proband with renal agenesis; ExAC: 0.1% (9/11538) Latino; ClinVar: 2 VUS
Eurofins Ntd Llc (ga)	RCV000727068	SCV000705348	uncertain significance	not provided	2017-02-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153409	SCV000890955	uncertain significance	Multiple endocrine neoplasia type 2A	2022-01-03	criteria provided, single submitter	clinical testing	The RET c.1699G>A (p.Asp567Asn) missense change has a maximum subpopulation frequency of 0.062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant occurs in the extracellular calmodulin-like motif (CaLM) in the cysteine rich domain, recently described as the location of a novel 3D cluster of oncogenic mutations in RET (PMID: 36166639). The in silico tool REVEL predicts a deleterious effect on protein function, and a molecular dynamics assay of mutations in CaLM and showed that this variant affects the conformational integrity of the RET-Ca2+ ion complex, underlying oncogenic properties which are increased in the presence of ligands/co-receptors that facilitate dimerization (PMID: 36166639). An in-vivo study showed that this variant is potentially druggable after existing RET-TKIs drugs, selpercatinib and pralsetinib, were shown to suppress the growth of NIH3T3 cells expressing p.Asp567Asn similar to their effect on NIH3T3 cells expressing known pathogenic mutations (PMID: 36166639). To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type IIA or type IIB. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Illumina Laboratory Services, Illumina	RCV001104478	SCV001261345	benign	Multiple endocrine neoplasia	2019-04-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001104479	SCV001261346	likely benign	Hirschsprung disease, susceptibility to, 1	2019-04-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001107242	SCV001264382	benign	Pheochromocytoma	2019-04-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001107243	SCV001264383	uncertain significance	Renal hypodysplasia/aplasia 1	2019-04-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000727068	SCV002499950	likely benign	not provided	2022-04-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21490379, 27834349, 27884173, 14633923)
Sema4, Sema4	RCV000163453	SCV002529942	likely benign	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000455280	SCV002550385	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272134	SCV002556561	uncertain significance	Familial medullary thyroid carcinoma	2021-03-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000727068	SCV003816116	uncertain significance	not provided	2020-10-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727068	SCV004042481	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	RET: BS2
Mendelics	RCV000163453	SCV004814090	likely benign	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001081705	SCV004838634	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 567 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant causes ectopic RET dimerization, activation of kinase activity and tumor formation in murine allograft growth assay (PMID: 36166639). This variant has been reported in a fetus affected with renal agenesis and an unaffected parent and in a Latina individual affected with adrenal medullary hyperplasia (PMID: 21490379, 32732076). This variant has been identified in 46/282764 chromosomes in the general population, including 22/35434 chromosomes in the Latino population, by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004542931	SCV004777010	likely benign	RET-related disorder	2024-02-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).