ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2371T>A (p.Tyr791Asn) (rs377767417)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411890 SCV000489783 uncertain significance Multiple endocrine neoplasia, type 2b 2016-02-02 criteria provided, single submitter clinical testing
Counsyl RCV000409436 SCV000489784 uncertain significance Multiple endocrine neoplasia, type 2a 2016-02-02 criteria provided, single submitter clinical testing
Invitae RCV000457504 SCV000543802 uncertain significance Multiple endocrine neoplasia, type 2 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 791 of the RET protein (p.Tyr791Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs377767417, ExAC 0.009%). This variant has been reported in both affected and unaffected individuals from families with Hirschsprung disease and medullary thyroid cancer, and there is no indication that this variant segregates with disease (PMID: 14557476, 17108762, 20013610, 23259706, 26559152, 28946813). It has also been observed in control individuals (PMID: 25425582). ClinVar contains an entry for this variant (Variation ID: 24939). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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.
Ambry Genetics RCV000566113 SCV000674775 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-08 criteria provided, single submitter clinical testing The p.Y791N variant (also known as c.2371T>A), located in coding exon 13 of the RET gene, results from a T to A substitution at nucleotide position 2371. The tyrosine at codon 791 is replaced by asparagine, an amino acid with dissimilar properties. This alteration was not found to segregate with disease in two kindreds with familial Hirschsprung disease and another kindred with familial medullary thyroid cancer (FMTC) (Ruiz-Ferrer M et al. Genet. Med. 2006 Nov;8(11):704-10; Frank-Raue K et al. Exp. Clin. Endocrinol. Diabetes 2010 Aug;118(8):550-3; Luzon-Toro B et al. Sci Pre 2015;5:16473). Based on protein sequence alignment, this amino acid position is not 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.
Mendelics RCV000409436 SCV000838400 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764900 SCV000896060 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
Research and Development, ARUP Laboratories RCV000021850 SCV000042516 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only First family report, at least 4 have the variant genotype: 1 HSCR. No evidence of MEN2 disease in family. Second family report, 2 have the variant genotype and were asymptomatic at 46yr and 72yr (PMID 20013610). Third family report, 1 has the variant genotype: MTC at 25 yr (MEN2008 meeting poster 52 Single French individual report: MTC at 58 yr (PMID 28946813).

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