ClinVar Genomic variation as it relates to human health

The RET c.1894G>A; p.Glu632Lys variant has been described in individuals affected with medullary thyroid cancer (MTC), Hirschsprung's disease, or pheochromocytoma (Carter 2012, Frank-Raue 2007, Han 2006, Romei 2015). It is reported as a variant of uncertain significance multiple times in ClinVar (Variation ID: 24920), and is observed in the general population at an overall frequency of 0.01% (24/247226 alleles) in the Genome Aggregation Database. The glutamic acid at codon 632 is moderately conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is tolerated. Due to limited information, the clinical significance of this variant cannot be determined with certainty. REFERENCES Carter TC et al. Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. J Hum Genet. 2012 Aug;57(8):485-93. Frank-Raue K et al. Change in the spectrum of RET mutations diagnosed between 1994 and 2006. Clin Lab. 2007;53(5-6):273-82. Han ZY et al. Mutation screening of RET proto-oncogene in Chinese sporadic patients with pheochromocytoma. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006 Jun;23(3):320-2. Romei C et al. Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clin Endocrinol (Oxf). 2015 Jun;82(6):892-9.

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17605401, 21479187, 16767674, 25440022, 34169762, 34570441, 31510104, 22648184, 30217742, 31159747, 14633923)

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 632 of the RET protein (p.Glu632Lys). This variant is present in population databases (rs377767407, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 17605401, 22648184, 25440022, 30217742, 31510104). ClinVar contains an entry for this variant (Variation ID: 24920). 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.

The p.Glu632Lys variant in RET has been reported in 2 individuals with Hirschsprung's disease, 1 individual with medullary thyroid carcinoma, and 1 individual tested for a hereditary cancer panel (Carter 2011 PMID: 22648184, Romei 2015 PMID: 25440022, Tang 2018 PMID: 30217742, Tsaousis 2019 PMID: 31159747). It has also been identified in 0.05% (14/30612) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4.

This alteration is classified as likely 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.

RET: PM1

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.