Submissions for variant NM_000465.4(BARD1):c.2002-1G>A

dbSNP: rs762601855

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523802	SCV000618706	likely pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of exon 11 which would disrupt the critical BRCT2 domain (PMID: 31803232), in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in an individual with melanoma in published literature (PMID: 33077847); This variant is associated with the following publications: (PMID: 33077847, 31803232)
Invitae	RCV000810463	SCV000950663	uncertain significance	Familial cancer of breast	2023-01-03	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with BARD1-related conditions. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 11 (Invitae). ClinVar contains an entry for this variant (Variation ID: 450160). This variant is present in population databases (rs762601855, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 10 of the BARD1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Color Diagnostics, LLC DBA Color Health	RCV001188789	SCV001355926	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -1 position of intron 10 of the BARD1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing, although this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. However, a different single-nucleotide variant with the equivalent predicted splicing impact, c.2002-2A>C, has been observed in an individual affected with triple-negative breast cancer (PMID: 25452441) and two individuals affected with early-onset breast cancer with positive family history for the disease (PMID: 31036035). The c.2002-1G>A variant has been identified in 1/250074 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 Likely Pathogenic.
Ambry Genetics	RCV001188789	SCV002718665	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	clinical testing	The c.2002-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 11 of the BARD1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000810463	SCV004043486	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.