ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1187C>T (p.Ser396Leu)

gnomAD frequency: 0.00006  dbSNP: rs781646869
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410233 SCV000489793 uncertain significance Multiple endocrine neoplasia type 2B 2016-03-11 criteria provided, single submitter clinical testing
Counsyl RCV000411297 SCV000489794 uncertain significance Multiple endocrine neoplasia type 2A 2016-03-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507135 SCV000605033 uncertain significance not specified 2017-03-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000574133 SCV000674874 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-23 criteria provided, single submitter clinical testing The p.S396L variant (also known as c.1187C>T), located in coding exon 6 of the RET gene, results from a C to T substitution at nucleotide position 1187. The serine at codon 396 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in an individual with Hirschsprung disease (Carter TC et al. J. Hum. Genet., 2012 Aug;57:485-93). This amino acid position is well 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000689688 SCV000817351 uncertain significance Multiple endocrine neoplasia, type 2 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 396 of the RET protein (p.Ser396Leu). This variant is present in population databases (rs781646869, gnomAD 0.006%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22648184). ClinVar contains an entry for this variant (Variation ID: 372081). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000411297 SCV004031161 uncertain significance Multiple endocrine neoplasia type 2A 2023-08-30 criteria provided, single submitter clinical testing The RET c.1187C>T (p.Ser396Leu) missense change has a maximum subpopulation frequency of 0.006% 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 functional studies have not been performed. This variant has been identified in an individual with Hirschsprung's disease (PMID: 22648184). This variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. 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.
Baylor Genetics RCV003463813 SCV004206719 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-03-27 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000689688 SCV004822878 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 396 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 variant in individuals affected with RET-related cancer in the literature. This variant has been identified in 8/282306 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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