Submissions for variant NM_020975.6(RET):c.2522C>T (p.Pro841Leu)

gnomAD frequency: 0.00015  dbSNP: rs149891333

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575365	SCV000664576	benign	Hereditary cancer-predisposing syndrome	2021-11-04	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000662511	SCV000785050	uncertain significance	Multiple endocrine neoplasia type 2A	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691895	SCV000819693	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 841 of the RET protein (p.Pro841Leu). This variant is present in population databases (rs149891333, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 2 or Hirschsprung's disease (PMID: 22648184, 24134185, 26071011). ClinVar contains an entry for this variant (Variation ID: 24947). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002477003	SCV000894527	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-01-03	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000782197	SCV000920670	uncertain significance	not provided	2018-09-16	criteria provided, single submitter	research
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000691895	SCV001775523	uncertain significance	Multiple endocrine neoplasia, type 2	2021-07-29	criteria provided, single submitter	clinical testing	The RET c.2522C>T (p.Pro841Leu) missense change has a maximum subpopulation frequency of 0.060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/10-43615108-C-T). This is higher than the reported incidence of multiple endocrine neoplasia type 2 (BS1). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with clinical features of multiple endocrine neoplasia type 2 or Hirschsprung's disease (PS4_supporting; PMID: 22648184, 24134185, 26071011). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS1, PS4_supporting, PP3.
Genetic Services Laboratory, University of Chicago	RCV001818175	SCV002064678	uncertain significance	not specified	2019-07-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662511	SCV004018075	uncertain significance	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
GeneDx	RCV000782197	SCV004021374	uncertain significance	not provided	2023-07-19	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: 25637381, 24055113, 33219105, 22837065, 21479187, 24134185, 20456320, 26071011, 22648184, 12566528, 14633923, 36251279, 36315513, 29338689, Decker and Peacock_1996)
CSER _CC_NCGL, University of Washington	RCV000148778	SCV000190516	uncertain significance	Aganglionic megacolon	2014-06-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV001535741	SCV001749859	not provided	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2A		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-08-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.