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

gnomAD frequency: 0.00024  dbSNP: rs139790943

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123327	SCV000166634	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 262 of the RET protein (p.Val262Ala). This variant is present in population databases (rs139790943, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with non-medullary thyroid carcinoma and Hirschsprung disease (PMID: 11955539, 31614935). ClinVar contains an entry for this variant (Variation ID: 41845). 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.
GeneDx	RCV000034777	SCV000279597	likely benign	not provided	2022-03-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 24336963, 11955539, 20956458, 22703879, 24055113, 15956201, 27884173, 31159747, 31614935)
Laboratory for Molecular Medicine, Mass General Brigham 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	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.
Counsyl	RCV000663296	SCV000786544	likely benign	Multiple endocrine neoplasia type 2A	2018-05-25	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	likely benign	Multiple endocrine neoplasia type 2A	2024-04-09	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000663296	SCV000891636	uncertain significance	Multiple endocrine neoplasia type 2A	2017-12-30	criteria provided, single submitter	curation
Illumina Laboratory Services, Illumina	RCV001103896	SCV001260709	uncertain significance	Hirschsprung disease, susceptibility to, 1	2019-11-27	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	RCV001103897	SCV001260710	likely benign	Pheochromocytoma	2019-11-27	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.
Illumina Laboratory Services, Illumina	RCV001103898	SCV001260711	uncertain significance	Renal hypodysplasia/aplasia 1	2019-11-27	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	RCV001104177	SCV001261020	likely benign	Multiple endocrine neoplasia	2019-11-27	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.
CeGaT Center for Human Genetics Tuebingen	RCV000034777	SCV002062909	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RET: BS2
Genetic Services Laboratory, University of Chicago	RCV000223157	SCV002068400	uncertain significance	not specified	2020-05-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RET gene demonstrated a sequence change, c.785T>C, in exon 4 that results in an amino acid change, p.Val262Ala. This sequence change has been described in the gnomAD database with a frequency of 0.043% in the South Asian sub-population (dbSNP rs139790943). The p.Val262Ala change has been reported in an individual with Hirshsprung's disease (PMID: 11955539). The p.Val262Ala change affects a moderately conserved amino acid residue located in a domain of the RET protein that is known to be functional. The p.Val262Ala substitution appears to be deleterious based on in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Val262Ala change remains unknown at this time.
Sema4, Sema4	RCV000573525	SCV002527924	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-03	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	Aganglionic megacolon	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004528165	SCV000807060	likely benign	RET-related disorder	2023-01-31	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).
Gharavi Laboratory, Columbia University	RCV000034777	SCV000920669	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research
Center of Medical Genetics and Primary Health Care	RCV001269367	SCV001448706	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing