ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9075701, 22429913, 23180660, 28698189, 27539727, 20516206, 27807060, 37321569, 25440022, 14633923, 30624503, 31510104, 30763276, 21810974, 33827484, 28946813)

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 918 of the RET protein (p.Met918Val). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of RET-related conditions (PMID: 20516206, 21810974, 25440022, 27807060, 28946813, 33827484). It has also been observed to segregate with disease in related individuals. However, it has been observed in individuals without personal history of RET-related conditions (PMID: 27807060, 21810974). One study that prospectively screened individuals with this variant identified several with medullary thyroid cancer or C-cell hyperplasia (PMID: 27807060). ClinVar contains an entry for this variant (Variation ID: 38614). 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. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 9075701, 21810974). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The p.M918V variant (also known as c.2752A>G), located in coding exon 16 of the RET gene, results from an A to G substitution at nucleotide position 2752. The methionine at codon 918 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in numerous individuals with a personal and/or family history of medullary thyroid carcinoma (MTC) (Cosci B et al. Endocr. Relat. Cancer. 2011 Oct;18:603-12; Lebeault M et al. Thyroid. 2017 12;27:1511-1522; Martins-Costa MC et al. Endocr. Relat. Cancer. 2016 12;23:909-920; Martins-Costa MC et al. Arch Endocrinol Metab. 2018;62:623-635; Romei C et al. Eur. J. Endocrinol. 2010 Aug;163:301-8). In one study, two unaffected family members were found to be carriers of the p.M918V variant and in vitro functional studies showed low to no transforming activity from this variant. Authors propose that this alteration may confer a more moderate disease risk as compared to other RET mutations (Cosci B et al. Endocr. Relat. Cancer. 2011 Oct;18:603-12). 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 supporting evidence, this alteration is likely pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.

In the published literature, this variant has been reported to segregate in affected families with medullary thyroid cancer (PMIDs: 30763276 (2019) and 33827484 (2021)) and C-cell hyperplasia (PMID: 27807060 (2016)). Functional analysis yielded inconclusive results regarding the impact of this variant on protein function (PMID: 9075701 (1997)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools (i.e., MutationTaster and PolyPhen-2) for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

Variant summary: RET c.2752A>G (p.Met918Val) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes. c.2752A>G has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma (e.g. Martins-Costa_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect showed a moderate effect on cell growth in transfected cells and a metabolomic profile consistent with a moderate risk (Veyrat-Durebex_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27807060, 30653460). ClinVar contains an entry for this variant (Variation ID: 38614). Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30624503, 21810974, 28946813, 33827484]. Functional studies indicate this variant impacts protein function [PMID: 30653460].