Submissions for variant NM_020975.6(RET):c.2887C>A (p.Leu963Ile)

gnomAD frequency: 0.00001  dbSNP: rs864622603

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206385	SCV000261281	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 963 of the RET protein (p.Leu963Ile). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 220609). 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.
Counsyl	RCV000662412	SCV000784843	uncertain significance	Multiple endocrine neoplasia type 2A	2016-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001016859	SCV001177858	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-28	criteria provided, single submitter	clinical testing	The p.L963I variant (also known as c.2887C>A), located in coding exon 17 of the RET gene, results from a C to A substitution at nucleotide position 2887. The leucine at codon 963 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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.
GeneDx	RCV003441786	SCV004167915	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923)
Baylor Genetics	RCV003462384	SCV004208719	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-08-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000206385	SCV004830376	uncertain significance	Multiple endocrine neoplasia, type 2	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 963 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 RET-related disorders in the literature. This variant has been identified in 1/31384 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.