Submissions for variant NM_007294.4(BRCA1):c.5194-2A>G

dbSNP: rs80358069

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131860	SCV000186915	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	The c.5194-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 18 in the BRCA1 gene. This mutation was detected in 2/82 Norwegian patients with breast and/or ovarian cancer who also had a family history that was concerning for hereditary breast and ovarian cancer (HBOC) syndrome (Møller P et al. Eur. J. Cancer. 2001 May;37:1027-32). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). 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; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000031228	SCV000266034	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000256055	SCV000322128	likely pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in full length transcript as well as the in-frame deletion of exon 19, located in the critical BRCT1 and BRCT2 domains (Chevalier 2020, Billaud 2021, UniProt); Observed in individuals with BRCA1-related cancers in the published literature (Shirts 2016, Park 2018, Rebbeck 2018, Wang 2019); Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay 2018); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5313-2A>G and IVS19-2A>G; This variant is associated with the following publications: (PMID: 28152038, 32124385, 14684619, 21523855, 26845104, 25085752, 25525159, 28111427, 31589614, 34749799, 30968603, 29673794, 29446198, 32341426, 33720054, 30209399)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031228	SCV000326210	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131860	SCV000683270	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 18 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Functional studies have reported conflicting results that this variant caused intermediate to loss of BRCA1 activity in haploid human cell proliferation assays (PMID: 30209399, 34749799). This variant has been reported in multiple individuals affected with breast cancer (PMID: 14684619, 22333603, 26845104, 30968603, 32341426; Color internal data). This variant has been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496913	SCV000699220	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5194-2A>G 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. 5/5 computational tools predict that the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes (gnomAD). c.5194-2A>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Esteban-Cardenosa_2004, Shirts_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000496913	SCV001579182	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 18 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80358069, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 10923033, 14684619, 21520333, 26845104). It has also been observed to segregate with disease in related individuals. This variant is also known as 5313-2A>G or IVS19-2A>G. ClinVar contains an entry for this variant (Variation ID: 37647). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798033	SCV002043451	pathogenic	Breast and/or ovarian cancer	2020-09-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031228	SCV004215128	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000256055	SCV004219443	pathogenic	not provided	2023-07-03	criteria provided, single submitter	clinical testing	The BRCA1 c.5194-2A>G variant (also known as IVS19-2A>G and 5313-2A>G) disrupts a canonical splice-acceptor site, and is predicted to result in the in-frame skipping of exon 19 and removal of a portion of the gene important for its structure or function. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 35918668 (2022), 32341426 (2020), 30968603 (2019), 29673794 (2018), 26845104 (2016), 14684619 (2004)). A saturation genome editing assay measuring cell survival classified this variant as non-functional (PMID: 30209399 (2018)). The frequency of this variant in the general population, 0.000004 (1/251484 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031228	SCV000053828	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-04-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031228	SCV000145388	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-21	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496913	SCV000587477	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353945	SCV000591591	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.5194-2A>G variant has been previously reported as disease-causing in the BIC and UMD databases and in the literature (Esteban-Cardeñosa 2003), however, no normal population controls were included in this study. This variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant -1 and -2 positions of the splice consensus sequence located in the 3' splice region of BRCA1. It is listed in the dbSNP database (ID#: rs80358069) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. In summary, based on the above information this variant is classified as pathogenic.
Brotman Baty Institute, University of Washington	RCV000031228	SCV001237899	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Center for Precision Medicine, Meizhou People's Hospital	RCV002250481	SCV002520900	likely pathogenic	Familial cancer of breast		no assertion criteria provided	literature only