Submissions for variant NM_000465.4(BARD1):c.2002-2A>C

dbSNP: rs876658260

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254847	SCV000322180	likely pathogenic	not provided	2016-06-28	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.2002-2A>C or IVS10-2A>C and consists of an A>C nucleotide substitution at the -2 position of intron 10 of the BARD1 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant was observed in an individual with triple negative breast cancer (Couch 2015). Based on the currently available evidence, we consider BARD1 c.2002-2A>C to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635764	SCV000757186	uncertain significance	Familial cancer of breast	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 of the BARD1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer and prostate cancer (PMID: 25452441, 31036035, 32338768, 33804961). ClinVar contains an entry for this variant (Variation ID: 265365). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics	RCV001014054	SCV001174713	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	The c.2002-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 11 in the BARD1 gene. This alteration has been detected in 1/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11). In addition, this alteration was identified in two individuals with personal and family history of breast cancer in a cohort of 4469 breast cancer index patients (Weber-Lassalle N et al. Breast Cancer Res., 2019 04;21:55). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of three amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000635764	SCV004044505	likely pathogenic	Familial cancer of breast	2023-05-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.