ClinVar Genomic variation as it relates to human health

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25801821, 28202063, 31034483)

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 211 of the VHL protein (p.Met211Leu). This variant is present in population databases (rs200019083, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer or renal cell carcinoma (PMID: 28202063, 31034483). ClinVar contains an entry for this variant (Variation ID: 182990). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Variant summary: VHL c.631A>C (p.Met211Leu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 276540 control chromosomes (gnomAD). The observed variant frequency is approximately 1.2 fold above the estimated maximal expected allele frequency for a pathogenic variant in VHL causing Von Hippel-Lindau Syndrome phenotype (2.1e-05), suggesting that the variant might be benign. The variant, c.631A>C, has been reported in the literature in individuals affected with Breast Cancer (Jalkh_2017). This report does not provide unequivocal conclusions about association of the variant with Von Hippel-Lindau Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x likely benign, 1x uncertain significance). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This missense variant replaces methionine with leucine at codon 211 of the VHL 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sporadic renal cell carcinoma along with a second VHL variant, c.3G>A, who lacks other manifestations or family history of von Hippel-Lindau syndrome (PMID: 31034483). This variant has been identified in 6/282108 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.

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.

The VHL c.631A>C variant is predicted to result in the amino acid substitution p.Met211Leu. This variant was reported in individuals with renal cell carcinoma or breast cancer (Jalkh et al 2017. PubMed ID: 28202063; Christensen MB et al 2019. PubMed ID: 31034483); however, variants in other genes were also reported. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.