ClinVar Genomic variation as it relates to human health

Variant summary: RET c.2078G>A (p.Arg693His) results in a non-conservative amino acid change in 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 250044 control chromosomes. c.2078G>A has been reported in the literature in at least one individual with an unspecified cancer (Guan_2015). This report does not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. At least one publication reports experimental evidence evaluating an impact on protein function (Guan_2020). In the context of oncogenesis, this variant was reported to result in increased RET phosphorylation, increased anchorage-independent growth, increased activation of downstream AKT/ERK signaling, and increased tumor size in mouse xenografts compared to wild-type. These results are potentially consistent with a gain-of-function mechanism for Multiple Endocrine Neoplasia Type 2. The following publications have been ascertained in the context of this evaluation (PMID: 25151137, 32293499). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 693 of the RET protein (p.Arg693His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary cancer (PMID: 25151137). ClinVar contains an entry for this variant (Variation ID: 959187). 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.

This missense variant replaces arginine with histidine at codon 693 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). A functional study has reported that this variant increased oncogenic transformation properties of RET in mammalian cell models (PMID: 32293499). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.

The p.R693H variant (also known as c.2078G>A), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide position 2078. The arginine at codon 693 is replaced by histidine, 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.