ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1678C>T (p.Pro560Ser)

gnomAD frequency: 0.00002  dbSNP: rs748852160
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000204252 SCV000260407 uncertain significance Multiple endocrine neoplasia, type 2 2024-10-24 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 560 of the RET protein (p.Pro560Ser). This variant is present in population databases (rs748852160, gnomAD 0.009%). 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: 220113). 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.
Mendelics RCV003491956 SCV000838388 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV002399762 SCV002712804 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-01 criteria provided, single submitter clinical testing he p.P560S variant (also known as c.1678C>T), located in coding exon 9 of the RET gene, results from a C to T substitution at nucleotide position 1678. The proline at codon 560 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for an 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). Based on the supporting evidence, the association of this alteration with Hirschsprung is unknown; however, the association of this alteration with MEN2 is unlikely.
Baylor Genetics RCV004567465 SCV005054211 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-01-11 criteria provided, single submitter clinical testing
GeneDx RCV005230078 SCV005874856 uncertain significance not provided 2024-08-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 35264596, 14633923, 25425582)

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