ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2522C>T (p.Pro841Leu) (rs149891333)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575365 SCV000664576 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-15 criteria provided, single submitter clinical testing The p.P841L variant (also known as c.2522C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2522. The proline at codon 841 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in individuals with Hirschsprung disease (HSCR) and congenital central hypoventilation syndrome (CCHS), however a direct association with pathogenicity has not been established (Carter TC et al. J. Hum. Genet., 2012 Aug;57:485-93; Fitze G et al. J. Med. Genet., 2003 Feb;40:E10; Hyndman BD et al. Hum. Mutat., 2013 Jan;34:132-42; Serra A et al. Ann. Hum. Genet., 2010 Jul;74:369-74). This alteration has been detected in a Korean patient diagnosed with an apparently sporadic pheochromocytoma at age 42 years (Kim JH et al. Clin Genet. 2014 Nov;86(5):482-6). This alteration has been detected by exome sequencing in multiple individuals unaffected with cancers/tumors or HSCR and classified as a variant of uncertain significance by collaborative groups curating the exome findings (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000662511 SCV000785050 uncertain significance Multiple endocrine neoplasia, type 2a 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV000691895 SCV000819693 uncertain significance Multiple endocrine neoplasia, type 2 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 841 of the RET protein (p.Pro841Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs149891333, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with clinical features of multiple endocrine neoplasia type 2 or Hirschsprung's disease (PMID: 26071011, 22648184, 24134185). ClinVar contains an entry for this variant (Variation ID: 24947). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000763647 SCV000894527 uncertain significance Congenital central hypoventilation; Hirschsprung disease 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2018-10-31 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 Clinical Genomics Lab, 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.
Research and Development, ARUP Laboratories RCV000021861 SCV000042527 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only First report, single individual: MTC only. Patient had unilateral MTC and no family history of MEN2. Second report, single Korean individual: Pheo only at 42 yr (PMID 24134185). Variant was also found in a HSCR patient (PMID 12566528).
CSER _CC_NCGL, University of Washington RCV000148778 SCV000190516 uncertain significance Hirschsprung disease 2014-06-01 no assertion criteria provided research
GenomeConnect - Invitae Patient Insights Network RCV001535741 SCV001749859 not provided Hirschsprung disease 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.

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