Submissions for variant NM_020975.6(RET):c.2754G>A (p.Met918Ile)

gnomAD frequency: 0.00001  dbSNP: rs753208054

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001967515	SCV002212575	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 918 of the RET protein (p.Met918Ile). This variant is present in population databases (rs753208054, gnomAD 0.003%). 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: 1431378). 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. This variant disrupts the p.Met918 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7906417, 8570194, 8918855, 9242375, 16715139, 20516206, 21810974, 27539324). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
All of Us Research Program, National Institutes of Health	RCV001967515	SCV004832704	uncertain significance	Multiple endocrine neoplasia, type 2	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces an invariant methionine with isoleucine at codon 918 in the tyrosine kinase catalytic domain of the RET protein (PMID: 7906417). 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 RET-related disorders in the literature. Two other missense variants, p.Met918Thr and p.Met918Val, have been reported as disease-causing in ClinVar (variation ID: 13919, 38614) based on both clinical and functional evidence for pathogenicity. Notably, the p.Met918Val variant which is more similar to the variant in question, p.Met918Ile, has been proposed to confer a more moderate disease risk as compared to more severely disrupted variants (PMID: 21810974; ClinVar SCV002752133.2). This variant has been identified in 2/251476 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.