Submissions for variant NM_000465.4(BARD1):c.2050A>T (p.Lys684Ter)

dbSNP: rs1559372578

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001014202	SCV001174884	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	The p.K684* pathogenic mutation (also known as c.2050A>T), located in coding exon 11 of the BARD1 gene, results from an A to T substitution at nucleotide position 2050. This changes the amino acid from a lysine to a stop codon within coding exon 11. This alteration occurs at the 3' terminus of the BARD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 94 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data).This alteration is located 5' to the BARD1 BRCT protein domain, which has been described as similar to those of the BRCA1 gene, and may be important for ligand binding (Birrane G et al. Biochemistry 2007 Jul; 46(26):7706-12). Further, an additional pathogenic mutation in the BARD1 gene, c.2148_2149delCA, is located 3’ to this alteration and has been described in a 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 alteration is interpreted as a disease-causing mutation.
Invitae	RCV001037336	SCV001200746	likely pathogenic	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys684*) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the BARD1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 820590). 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. 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.
Myriad Genetics, Inc.	RCV001037336	SCV004044082	pathogenic	Familial cancer of breast	2023-05-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV001014202	SCV004362621	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BARD1 gene, creating a premature translation stop signal at codon 684. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as truncated protein lacking the functional BRCT2 domain (a.a. 667-777) that is critical for BARD1 protein function (PMID: 17848578, 30925164). To our knowledge, this variant has not been reported in individuals affected with BARD1-related disorders in the literature. This variant has been identified in 1/251172 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.