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

dbSNP: rs879254139

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235953	SCV000293620	likely pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: abnormal splicing (Casadei et al., 2019); This variant is associated with the following publications: (PMID: 31843900, 31036035, 33804961, 33809641)
Invitae	RCV000552182	SCV000632971	pathogenic	Familial cancer of breast	2023-11-28	criteria provided, single submitter	clinical testing	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). 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, ovarian or prostate cancer (PMID: 31036035, 31843900). ClinVar contains an entry for this variant (Variation ID: 246176). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 31843900; Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000565922	SCV000660810	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	The c.159-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 2 of the BARD1 gene. In one study, this alteration was detected in 1/4469 German breast cancer patients (Weber-Lassalle N et al. Breast Cancer Res., 2019 04;21:55). This variant was not reported in population-based 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 acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). A published RNA study also identified abnormal splicing associated with this variant (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). 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.
Color Diagnostics, LLC DBA Color Health	RCV000565922	SCV000688135	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-09	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 1 of the BARD1 gene. An RNA study has reported two aberrant transcripts found uniquely in carrier and absent in healthy control that are expected to produce absent or non-functional protein product (PMID: 31843900). This variant also has been reported in one individual each affected with breast and ovarian cancer (PMID: 31036035, 31843900). This variant has not been identified 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 Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587901	SCV000696749	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-02-07	criteria provided, single submitter	clinical testing	Variant summary: The BARD1 c.159-1G>T variant involves the alteration of a conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant. 4/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121314 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, a clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000552182	SCV002814602	pathogenic	Familial cancer of breast	2021-11-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000235953	SCV002822789	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	BARD1: PVS1, PM2
Institute of Human Genetics, University of Leipzig Medical Center	RCV000552182	SCV003804664	pathogenic	Familial cancer of breast	2022-12-23	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235953	SCV004026029	likely pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing	PVS1
Myriad Genetics, Inc.	RCV000552182	SCV004044203	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.
Baylor Genetics	RCV000552182	SCV004217203	likely pathogenic	Familial cancer of breast	2023-08-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235953	SCV004221609	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	The BARD1 c.159-1G>T variant disrupts a canonical splice-acceptor site and interferes with normal BARD1 mRNA splicing. This variant has been reported in the published literature in affected individuals with breast cancer (PMIDs: 31036035 (2019) and 33471991 (2021)), ovarian and prostate cancer (PMID: 31843900 (2019)), b-cell neoplasms (PMID: 33809641 (2021)), as well as in a healthy individual (PMID: 33471991 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
King Laboratory, University of Washington	RCV000552182	SCV001251317	pathogenic	Familial cancer of breast	2019-09-01	no assertion criteria provided	research