Submissions for variant NM_000465.4(BARD1):c.1903+1G>A

dbSNP: rs876660237

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001013627	SCV001174236	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	clinical testing	The c.1903+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 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 donor 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; however, the impacted region is critical for protein function (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001013627	SCV001340711	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 9 of the BARD1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although the RNA splicing effect of this variant has not been reported, the skipping of the adjacent exon 9 is predicted to cause an in-frame deletion encompassing structural motifs in the BRCT domain that is required for the chromosome stability and homology-directed repair activities of the BARD1 protein (PMID: 17550235, 17848578). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251054 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.
CeGaT Center for Human Genetics Tuebingen	RCV002511014	SCV002822788	likely pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BARD1: PVS1:Strong, PM2
Myriad Genetics, Inc.	RCV003336240	SCV004044264	likely pathogenic	Familial cancer of breast	2023-05-24	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.
Invitae	RCV003336240	SCV004524497	likely pathogenic	Familial cancer of breast	2023-04-08	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 820310). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects a donor splice site in intron 9 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).