Submissions for variant NM_020975.6(RET):c.3233C>T (p.Thr1078Met)

gnomAD frequency: 0.00002  dbSNP: rs762952212

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466142	SCV000543843	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1078 of the RET protein (p.Thr1078Met). This variant is present in population databases (rs762952212, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical symptoms of RET-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 405556). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV001770303	SCV001993427	uncertain significance	not provided	2024-01-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with clear cell renal carcinoma (PMID: 29684080); This variant is associated with the following publications: (PMID: 36657661, 14633923, 35383193, 25922291, 29684080)
Genetic Services Laboratory, University of Chicago	RCV001821238	SCV002066807	uncertain significance	not specified	2021-08-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RET gene demonstrated a sequence change, c.3233C>T, in exon 20 that results in an amino acid change, p.Thr1078Met. This sequence change does not appear to have been previously described in patients with RET-related disorders. This sequence change has been described in the gnomAD database with a low population frequency of 0.002% (dbSNP rs762952212). The p.Thr1078Met change affects a poorly conserved amino acid residue of the RET protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr1078Met substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr1078Met change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821238	SCV002103956	uncertain significance	not specified	2022-02-07	criteria provided, single submitter	clinical testing	Variant summary: RET c.3233C>T (p.Thr1078Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251490 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3233C>T in individuals affected with Multiple Endocrine Neoplasia Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291627	SCV002584585	uncertain significance	Multiple endocrine neoplasia type 2A	2022-08-29	criteria provided, single submitter	clinical testing	The RET c.3233C>T (p.Thr1078Met) missense change has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type 2. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV002446783	SCV002611316	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-27	criteria provided, single submitter	clinical testing	The p.T1078M variant (also known as c.3233C>T), located in coding exon 20 of the RET gene, results from a C to T substitution at nucleotide position 3233. The threonine at codon 1078 is replaced by methionine, an amino acid with similar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a MEN2 disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely.
Baylor Genetics	RCV003463863	SCV004208669	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-09-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000466142	SCV004838731	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1078 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004740228	SCV005349908	uncertain significance	RET-related disorder	2024-09-09	no assertion criteria provided	clinical testing	The RET c.3233C>T variant is predicted to result in the amino acid substitution p.Thr1078Met. This variant was reported in an individual with kidney renal clear cell carcinoma (Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/405556/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.