ClinVar Genomic variation as it relates to human health

In the published literature, this variant has been reported in individuals with breast cancer, prostate cancer, and unaffected controls (PMIDs: 27424772 (2016), 23064873 (2013)). The frequency of this variant in the general population, 0.00026 (34/128928 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools 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, we are unable to determine the clinical significance of this variant.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 217 of the HOXB13 protein (p.Arg217Cys). This variant is present in population databases (rs139475791, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast and prostate cancer (PMID: 23064873, 27424772, 32546843). ClinVar contains an entry for this variant (Variation ID: 483473). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HOXB13 protein function with a positive predictive value of 80%. 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.R217C variant (also known as c.649C>T), located in coding exon 2 of the HOXB13 gene, results from a C to T substitution at nucleotide position 649. The arginine at codon 217 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in two unrelated European families with familial prostate cancer; however, authors state that the variant did not co-segregate with disease in either family (Xu J et al. Hum. Genet. 2013 Jan;132:5-14). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in two prostate cancer kindreds, but was reported to not segregate with disease (PMID: 23064873); Case-control studies show no significant association with breast cancer (PMID: 27424772, 32546843); This variant is associated with the following publications: (PMID: 27424772, 28798948, 28072499, 22841674, 22236224, 34609407, 19389631, 8756292, 23064873, 32546843)

The HOXB13 c.649C>T variant is predicted to result in the amino acid substitution p.Arg217Cys. This variant has been reported in two families with prostate cancer, but did not co-segregate with disease (Xu et al. 2013. PubMed ID: 23064873). It has been reported in a prostate cancer cohort study assessing HOXB13 haplotypes: however, no clinical information was provided (Karlsson et al. 2014. PubMed ID: 22841674). This variant has also been reported in two large breast cancer cohort studies and determined to confer no increased risk of female breast cancer (Liu et al. 2016. PubMed ID: 27424772; Liu et al. 2020. PubMed ID: 32546843). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/483473). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.