ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2066C>T (p.Ser689Phe)

gnomAD frequency: 0.00001  dbSNP: rs989429215
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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 RCV000822677 SCV000963487 uncertain significance Multiple endocrine neoplasia, type 2 2023-06-04 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 689 of the RET protein (p.Ser689Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 664562). 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.
Ambry Genetics RCV003169037 SCV003858491 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-20 criteria provided, single submitter clinical testing The p.S689F variant (also known as c.2066C>T), located in coding exon 11 of the RET gene, results from a C to T substitution at nucleotide position 2066. The serine at codon 689 is replaced by phenylalanine, an amino acid with highly dissimilar 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.
All of Us Research Program, National Institutes of Health RCV000822677 SCV005430370 uncertain significance Multiple endocrine neoplasia, type 2 2024-02-22 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 689 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 in individuals affected with RET-related disorders in the literature. This variant has been identified in 2/281728 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.

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