ClinVar Miner

Submissions for variant NM_020975.6(RET):c.31C>A (p.Leu11Met)

gnomAD frequency: 0.00003  dbSNP: rs587780812
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575741 SCV000674837 benign Hereditary cancer-predisposing syndrome 2023-07-26 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000689589 SCV000817246 uncertain significance Multiple endocrine neoplasia, type 2 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 11 of the RET protein (p.Leu11Met). 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: 486316). 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.
Genetic Services Laboratory, University of Chicago RCV001821691 SCV002068971 likely benign not specified 2018-04-24 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000575741 SCV002527907 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-15 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV000689589 SCV004838618 likely benign Multiple endocrine neoplasia, type 2 2023-12-18 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004530620 SCV004739289 uncertain significance RET-related disorder 2024-07-11 no assertion criteria provided clinical testing The RET c.31C>A variant is predicted to result in the amino acid substitution p.Leu11Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/486316/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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