Submissions for variant NM_020975.6(RET):c.3052C>T (p.Leu1018Phe)

gnomAD frequency: 0.00001  dbSNP: rs766330880

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654577	SCV000776471	uncertain significance	Multiple endocrine neoplasia, type 2	2025-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1018 of the RET protein (p.Leu1018Phe). This variant is present in population databases (rs766330880, gnomAD 0.01%). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 33827484). ClinVar contains an entry for this variant (Variation ID: 543741). 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 disruptive. 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.
Mendelics	RCV000709125	SCV000838408	uncertain significance	Multiple endocrine neoplasia type 2A	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018329	SCV001179553	likely benign	Hereditary cancer-predisposing syndrome	2024-08-13	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.
Illumina Laboratory Services, Illumina	RCV001106020	SCV001263044	uncertain significance	Pheochromocytoma	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001106021	SCV001263045	uncertain significance	Renal hypodysplasia/aplasia 1	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001106022	SCV001263046	uncertain significance	Hirschsprung disease, susceptibility to, 1	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001106023	SCV001263047	likely benign	Multiple endocrine neoplasia	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV003318621	SCV004022723	uncertain significance	not provided	2023-07-21	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: 14633923, 33827484)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493698	SCV004243366	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000654577	SCV004838712	uncertain significance	Multiple endocrine neoplasia, type 2	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1018 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with medullary thyroid cancer (PMID: 33827484). This variant has been identified in 14/251434 chromosomes in the general 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.
Baylor Genetics	RCV001106022	SCV005054214	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-01-05	criteria provided, single submitter	clinical testing