Submissions for variant NM_000465.4(BARD1):c.159-1G>A

dbSNP: rs879254139

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702035	SCV000830863	pathogenic	Familial cancer of breast	2023-09-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BARD1 protein in which other variant(s) (p.Cys71Tyr) have been determined to be pathogenic (PMID: 26350354, 29367421). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 31843900). ClinVar contains an entry for this variant (Variation ID: 578893). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the BARD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780948	SCV000918623	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-04-27	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.159-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245890 control chromosomes (gnomAD). To our knowledge, no occurrence of c.159-1G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000702035	SCV004044295	likely pathogenic	Familial cancer of breast	2023-05-18	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.
Ambry Genetics	RCV004026577	SCV005035658	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The c.159-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 2 of the BARD1 gene. 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. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.