Submissions for variant NM_020975.6(RET):c.2477A>C (p.Tyr826Ser)

gnomAD frequency: 0.00004  dbSNP: rs34617196

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205464	SCV000261139	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 826 of the RET protein (p.Tyr826Ser). This variant is present in population databases (rs34617196, gnomAD 0.008%). This missense change has been observed in individual(s) with medullary thyroid carcinoma and C-cell hyperplasia (PMID: 27099842). ClinVar contains an entry for this variant (Variation ID: 220530). 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.
Counsyl	RCV000411008	SCV000490097	uncertain significance	Multiple endocrine neoplasia type 2B	2016-11-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000412172	SCV000490098	uncertain significance	Multiple endocrine neoplasia type 2A	2016-11-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000679731	SCV000567961	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in trans with the pathogenic RET variant V804M in a patient with medullary thyroid cancer who had both maternal and paternal family histories of thyroid cancer (PMID: 27099842); This variant is associated with the following publications: (PMID: 24336963, 26206375, 27527004, 14633923, 17344846, 27099842)
Ambry Genetics	RCV001015653	SCV001176512	likely benign	Hereditary cancer-predisposing syndrome	2021-10-28	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.
Myriad Genetics, Inc.	RCV000412172	SCV004018074	likely benign	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320137	SCV004024380	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462382	SCV004208648	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-10-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739598	SCV000807028	uncertain significance	RET-related disorder	2024-07-09	no assertion criteria provided	clinical testing	The RET c.2477A>C variant is predicted to result in the amino acid substitution p.Tyr826Ser. This variant resides in a well-conserved domain where missense variants are known to be pathogenic for RET-associated disorders. This variant has been reported in a family where the proband presented with medullary thyroid carcinoma. In addition, this individual had a second RET variant that is known to be pathogenic. Reduced penetrance and variable expressivity are well-documented in RET-associated disorders and was apparent in this family. The proband’s mother, who was heterozygous for this variant, had a history of microfollicular thyroid adenomas while other heterozygotes did not present with any clinical signs of medullary thyroid disease (Karrasch et al. 2016. PubMed ID: 27099842). This variant is reported in 0.0081% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/220530/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.