ClinVar Genomic variation as it relates to human health

Normal stop codon changed to a Lysine codon, leading to the addition of 96 amino acids at the C-terminus; Case-control studies in individuals with African ancestry are conflicting with respect to overall prostate cancer risk, but suggest that this variant is associated with early-onset or aggressive disease in affected individuals (PMID: 34799695, 35031163, 37806842); Observed in individuals with prostate or breast cancer, but also in unaffected controls (PMID: 22781434, 32040869, 36446039); Published functional studies using patient cells suggest a gain-of-function effect resulting in elevated expression of cyclin B1 and c-Myc (PMID: 37806842); This variant is associated with the following publications: (PMID: 24239177, 22781434, 32040869, 35031163, 33804961, 34799695, 37806842, 36446039)

Variant summary: HOXB13 c.853delT (p.X285LysfsX97) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.00015 in 251424 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 264 fold of the estimated maximal expected allele frequency for a pathogenic variant in HOXB13 causing Prostate Cancer phenotype (8.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.853delT has been reported in the literature in individuals affected with Prostate/Breast Cancer and in unaffected controls (example, Akbari_2012, Marlin_2020). It has also been reported as significantly associated with early onset and aggressive prostate cancer in individuals of African American ancestry (examples: Dars_2022 and Na_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Prostate Cancer. 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 and classified the variant as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change disrupts the translational stop signal of the HOXB13 mRNA. It is expected to extend the length of the HOXB13 protein by 96 additional amino acid residues. This variant is present in population databases (rs77179853, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This protein extension has been observed in individuals with prostate cancer, however it has also been identified in unaffected individuals. In a case-control study involving 10,477 prostate cancer patients and 9,688 controls with African ancestry, men carrying this variant had a 2.4 fold higher relative risk of prostate cancer compared with non-carriers (95 % CI 1.5-3.9)(PMID: 35031163, Invitae). Also, carriers have increased risk of early onset, more aggressive, and advanced disease (PMID: 35031163, 34799695). Both population studies and haplotype analyses suggest that this variant is a West African founder mutation, explaining the higher frequency in these populations (PMID: 35031163). ClinVar contains an entry for this variant (Variation ID: 182506). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele.

The c.853delT variant, located in coding exon 2 of the HOXB13 gene, results from a deletion of one nucleotide at nucleotide position 853, disrupting the native stop codon and extending the protein by 96 amino acids (p.*285Kext*96). This alteration has been reported in one of 200 individuals with prostate cancer and in one of 160 control subjects of African ancestry, and has also been reported in additional prostate cancer cohorts in men with primarily West African ancestry (Akbari MR et al. J. Natl. Cancer Inst. 2012 Aug;104:1260-2; Marlin R et al. Prostate 2020 05;80(6):463-470; Na R et al. Br J Cancer 2022 Mar;126(5):791-796). Case control studies show a positive association of this variant with prostate cancer (Darst BF et al. Eur Urol 2022 May;81(5):458-462; Ambry internal data; external communication), with published estimations that male carriers of the c.853delT variant have an approximate 2.4 to 4-fold risk of prostate cancer compared to the general population (Darst et al.). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The HOXB13 c.853delT variant is predicted to result in extension of the open reading frame (p.*285Lysext*96). This variant has been documented in multiple patients with prostate cancer in the literature. Statistical analyses suggest that this variant may confer increased susceptibility to aggressive prostate cancer, with onset at an earlier age (Akbari et al. 2012. PubMed ID:  22781434; Marlin et al. 2020. PubMed ID: 32040869; Na et al. 2021. PubMed ID: 34799695). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182506/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.