ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2875C>T (p.Arg959Trp)

gnomAD frequency: 0.00002  dbSNP: rs587778658
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409726 SCV000489781 uncertain significance Multiple endocrine neoplasia type 2B 2016-02-02 criteria provided, single submitter clinical testing
Counsyl RCV000410787 SCV000489782 uncertain significance Multiple endocrine neoplasia type 2A 2016-02-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000559400 SCV000658459 uncertain significance Multiple endocrine neoplasia, type 2 2024-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 959 of the RET protein (p.Arg959Trp). This variant is present in population databases (rs587778658, gnomAD 0.006%). 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: 135180). 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 RCV002433615 SCV002751127 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-02 criteria provided, single submitter clinical testing The p.R959W variant (also known as c.2875C>T), located in coding exon 17 of the RET gene, results from a C to T substitution at nucleotide position 2875. The arginine at codon 959 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx RCV004783748 SCV005396425 uncertain significance not provided 2024-05-08 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; Identified in healthy individuals undergoing whole genome sequencing (PMID: 24728327); This variant is associated with the following publications: (PMID: 14633923, 24728327)
All of Us Research Program, National Institutes of Health RCV000559400 SCV005430401 uncertain significance Multiple endocrine neoplasia, type 2 2024-06-17 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 959 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282842 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.
ITMI RCV000121982 SCV000086192 not provided not specified 2013-09-19 no assertion provided reference population

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