Submissions for variant NM_000465.4(BARD1):c.1314+1G>A

dbSNP: rs753785671

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566497	SCV000660876	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-12	criteria provided, single submitter	clinical testing	The c.1314+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the BARD1 gene. This variant was identified in 1/937 Chinese breast cancer patients undergoing multigene panel testing (Li JY et al. Int J Cancer, 2019 01;144:281-289). This variant was also detected in a women with ovarian cancer that was part of a Spanish cohort of 4015 index patients with a personal or family history suggestive of hereditary breast and/or ovarian cancer (Rofes P et al. Genes (Basel), 2021 Jan;12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635897	SCV000757323	likely pathogenic	Familial cancer of breast	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 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). This variant is present in population databases (rs753785671, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with neuroblastoma or personal and/or family history of breast and/or ovarian cancer (PMID: 27009842, 29752822, 33498765). ClinVar contains an entry for this variant (Variation ID: 479152). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (internal data). 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.	RCV000635897	SCV004044292	likely pathogenic	Familial cancer of breast	2023-05-22	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.
Baylor Genetics	RCV000635897	SCV004217314	pathogenic	Familial cancer of breast	2023-12-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003488698	SCV004238490	likely pathogenic	not provided	2023-06-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003488698	SCV005625692	pathogenic	not provided	2024-05-17	criteria provided, single submitter	clinical testing	The BARD1 c.1314+1G>A variant disrupts a canonical splice-donor site, and has been described to cause out-of-frame exon skipping based on RNA analysis (PMID: 33498765 (2021)). This variant has been reported in individuals with breast cancer (PMID: 29752822 (2018)), ovarian cancer (PMID: 33498765 (2021)), and neuroblastoma (PMID: 27009842 (2016)). The frequency of this variant in the general population, 0.000004 (1/250606 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056193	SCV005726331	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-14	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1314+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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of BARD1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a cryptic 3' acceptor site. One predict the variant creates a 3' acceptor site. The variant allele was found at a frequency of 4e-06 in 250606 control chromosomes. c.1314+1G>A has been reported in the literature in individuals with a personal or family history of Hereditary Breast And Ovarian Cancer Syndrome (Feliubadalo_2019, Li_2019, Rofes_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 30927264, 29752822, 33498765). ClinVar contains an entry for this variant (Variation ID: 479152). Based on the evidence outlined above, the variant was classified as likely pathogenic.