ClinVar Miner

Submissions for variant NM_020975.6(RET):c.731C>T (p.Thr244Ile)

gnomAD frequency: 0.00002  dbSNP: rs145970248
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000557609 SCV000658496 uncertain significance Multiple endocrine neoplasia, type 2 2025-01-14 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 244 of the RET protein (p.Thr244Ile). This variant is present in population databases (rs145970248, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of autosomal dominant multiple endocrine neoplasia type 2 (PMID: 36407031). ClinVar contains an entry for this variant (Variation ID: 477385). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV001026272 SCV001188617 likely benign Hereditary cancer-predisposing syndrome 2024-02-07 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.
Fulgent Genetics, Fulgent Genetics RCV002506371 SCV002817069 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2021-10-25 criteria provided, single submitter clinical testing

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