ClinVar Genomic variation as it relates to human health

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 730 of the BARD1 protein (p.Gln730Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer or neuroblastoma (PMID: 27009842, 29752822). ClinVar contains an entry for this variant (Variation ID: 229888). 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.

The p.Q730P variant (also known as c.2189A>C), located in coding exon 11 of the BARD1 gene, results from an A to C substitution at nucleotide position 2189. The glutamine at codon 730 is replaced by proline, an amino acid with similar properties. This variant was reported in a cohort of Chinese patients at a high risk for breast cancer (Li JY et al. Int. J. Cancer. 2019 01;144:281-289). Additionally, this alteration was identified in an individual diagnosed with breast cancer (Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55). This alteration was also seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). 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.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.