ClinVar Genomic variation as it relates to human health

Variant summary: BARD1 c.1935_1954dup20 (p.Glu652ValfsX69) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One report in the literature indicates that the variant does not activate nonsense mediated decay, as RT-PCR analysis showed equal amounts of the mutant and wild-type alleles expressed in leukocytes from individuals with the variant (DeBrakeleer_2010). The variant allele was found at a frequency of 6.4e-05 in 251374 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer (6.4e-05 vs 0.00025), allowing no conclusion about variant significance. c.1935_1954dup20 has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. DeBrakeleer_2010, Couch_2015, Weber-Lassalle_2019). These data indicate that the variant is very likely to be associated with disease. The variant has also been found in at least one patient with pancreatic cancer (Smith_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This frameshift variant alters the translational reading frame of the BARD1 mRNA and causes the premature termination of BARD1 protein synthesis. The frequency of this variant in the general population, 0.00012 (15/129114 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with breast cancer (PMIDs: 31036035 (2019), 26681312 (2015), 25452441 (2015), 20077502 (2010)). Based on the available information, this variant is classified as pathogenic.

This variant inserts 20 nucleotides in exon 10 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to disrupt the last 126 amino acids of the BARD1 protein, including the functionally important BRCT2 domain (a.a. 667-777) (PMID: 17848578) and is likely to result in a non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 20077502, 25452441, 26681312, 31036035). This variant has also been reported in at least one individual with neuroblastoma (PMID: 33598691). This variant has been identified in 17/282768 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The c.1935_1954dup20 pathogenic mutation, located in coding exon 10 of the BARD1 gene, results from a duplication of 20 nucleotides from positions 1935 to 1954, causing a translational frameshift with a predicted alternate stop codon. This mutation has previously been reported in a high risk breast/ovarian cancer family from Belgium (De Brakeleer S et al. Hum. Mutat. 2010 Mar;31(3):E1175-85) and in 3 of 1824 triple negative breast cancer patients unselected for family history (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11, Supplementary Data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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

This sequence change creates a premature translational stop signal (p.Glu652Valfs*69) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acid(s) of the BARD1 protein. This variant is present in population databases (rs587780024, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 20077502, 25452441, 26681312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127725). RT-PCR analysis has shown that this variant did not activate nonsense mediated decay, as equal amounts of the mutant and wild-type alleles were expressed in the leukocytes of affected individuals (PMID: 20077502). This truncating variant does lead to the loss of the last 126 amino acids of the BARD1 protein (Glu652-Ser777), removing completely the most C-terminal of the two BRCT repeats (residues 669-777) (PMID: 26315354, 17550235). While the functional significance of deleting the second BRCT domain has not been addressed experimentally, studies suggest that both BRCT repeats in BARD1 are necessary for its normal functioning (PMID: 17550235, 26738429, 17848578). For these reasons, this variant has been classified as Pathogenic.

Frameshift variant predicted to result in abnormal protein length as the last 126 amino acids are replaced with 68 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with personal or family history of breast and/or ovarian cancer (PMID: 20077502, 25452441, 28888541, 29790872, 31173646, 31036035, 35626031); This variant is associated with the following publications: (PMID: 31341520, 26681312, 28008555, 26738429, 28152038, 20077502, 25452441, 26556299, 26315354, 17848578, 26546047, 29922827, 29790872, 31036035, 31173646, 33099839, 32679805, 33598691, 35626031, 32923906, 36187937, 28888541, 34326862, 35969835, 17550235, 37688579)

Variant interpreted as Pathogenic and reported on 09-21-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.