ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1612A>G (p.Thr538Ala)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV003296600 SCV004000302 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-17 criteria provided, single submitter clinical testing The p.T538A variant (also known as c.1612A>G), located in coding exon 8 of the RET gene, results from an A to G substitution at nucleotide position 1612. The threonine at codon 538 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. 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.
Fulgent Genetics, Fulgent Genetics RCV005047515 SCV005674381 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2024-01-09 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005102700 SCV005772058 uncertain significance Multiple endocrine neoplasia, type 2 2024-12-16 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 538 of the RET protein (p.Thr538Ala). This variant is present in population databases (rs746279995, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 2562607). 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.

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