ClinVar Genomic variation as it relates to human health

Nonsense variant predicted to result in protein truncation as the last 30 amino acids are lost, and other downstream truncating variants have been reported to affect protein function (Adamovich et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); Observed in an individual with fallopian tube or ovarian cancer (Walsh et al., 2011; Lilyquist et al., 2017); This variant is associated with the following publications: (PMID: 30925164, 29922827, 28888541, 22006311)

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the C-terminal BRCT domain of BARD1 protein, which is required for chromosome stability and homology-directed repair (PMID: 17848578). A different variant (p.Val767fs) that lies downstream of this variant has been reported to affect BARD1 protein function (PMID: 30925164), this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 187542). This premature translational stop signal has been observed in individual(s) with fallopian tube cancer (PMID: 22006311). This variant is present in population databases (rs786203811, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ile717Glnfs*12) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the BARD1 protein.

The c.2148_2149delCA pathogenic mutation, located in coding exon 11 of the BARD1 gene, results from a deletion of two nucleotides at nucleotide positions 2148 to 2149, causing a translational frameshift with a predicted alternate stop codon (p.I717Qfs*12). This alteration occurs at the 3' terminus of theBARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 7% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Additionally, this alteration impacts the BRCT domain of BARD1, which has been shown to be necessary for homology-directed DNA repair (Laufer M et al. J Biol Chem, 2007 Nov;282:34325-33, Adamovich AI et al. PLoS Genet, 2019 03;15:e1008049). This alteration has been reported in one patient diagnosed with fallopian tube cancer at age 53 (Walsh, T el al. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

The BARD1 p.I717Qfs*12 variant was identified in one individual with fallopian tube serous carcinoma (Walsh_2011_PMID: 22006311). The variant was identified in dbSNP (ID: rs786203811) and ClinVar (classified as pathogenic by Ambry Genetics and as uncertain significance by Invitae). The variant was not identified in Cosmic. The variant was identified in control databases in 1 of 236840 chromosomes at a frequency of 0.000004222 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 1 of 102654 chromosomes (freq: 0.00001), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.2148_2149del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 717 and leads to a premature stop codon 12 codons downstream, instead of the normal stop codon at 778. This variant occurs in the last exon of the BARD1 gene and results in less than a 10% loss of the protein, therefore the function of this variant is currently unclear. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.