Submissions for variant NM_007294.4(BRCA1):c.302-2del

gnomAD frequency: 0.00001  dbSNP: rs273899695

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077534	SCV001161544	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048047	SCV000076060	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-14	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 5 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and ovarian cancer (PMID: 9333265, 10486320, 12815598, 16619214, 20104584). This variant is also known as 421-2delA and IVS6-2delA. ClinVar contains an entry for this variant (Variation ID: 54753). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 12815598, 16619214). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130037	SCV000184863	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-25	criteria provided, single submitter	clinical testing	The c.302-2delA intronic pathogenic mutation results from the deletion of one nucleotide two nucleotides upstream from coding exon 5 of the BRCA1 gene. This mutation has been described in multiple families with hereditary breast and ovarian cancer (HBOC) syndrome (Shattuck-Eidens D et al. JAMA. 1997 Oct;278:1242-50; Gayther SA et al. Am. J. Hum. Genet. 1999 Oct;65:1021; Tesoriero AA et al. Hum. Mutat. 2005 Nov;26:495; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620). RNA studies have also demonstrated that this alteration results in an aberrant transcript that results in the deletion of 10 base pairs from coding exon 5 and results in a frameshift (Ambry internal data; Chen X et al. Hum. Mutat. 2006 May;27:427-35; Southey MC et al. Hum. Mutat. 2003 Jul;22:86-91). This alteration was classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology, and case-control data (Parsons MT et al. Hum. Mutat. 2019 09;40(9):1557-1578). Of note, this alteration is also designated as 421-2delA and IVS6-2delA in published literature. 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077534	SCV000325536	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482044	SCV000566338	pathogenic	not provided	2024-03-12	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in aberrant splicing leading to a predicted null allele in a gene for which loss-of-function is a known mechanism of disease (PMID: 12815598, 16619214); Observed in several individuals with personal and/or family history consistent with pathogenic variants in this gene (PMID: 9333265, 10486320, 12815598, 16211554, 16619214, 33758026); Not observed at significant frequency in large population cohorts (gnomAD); Multifactorial likelihood analysis suggests this variant is pathogenic (PMID: 31131967); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 421-2delA and IVS6-2delA; This variant is associated with the following publications: (PMID: 10486320, 12815598, 9333265, 16211554, 21702907, 16619214, 18712473, 31447099, 30787465, 33087929, 33758026, 31131967)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482044	SCV000600313	pathogenic	not provided	2016-11-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048047	SCV000967734	pathogenic	Hereditary breast ovarian cancer syndrome	2018-03-16	criteria provided, single submitter	clinical testing	The c.302-2delA variant in BRCA1 has been reported in at least 16 individuals wi th breast and/or ovarian cancer (Shattuck-Eidens 1997, Gayther 1999, Southey 200 3, Chen 2006, Borg 2010, BIC database [https://research.nhgri.nih.gov/bic/]) and segregated with disease in at least 9 affected relatives from 1 family (Southey 2003). This variant has also been reported by other clinical laboratories in C linVar (Variation ID# 54753) and was absent from large population databases. Th e c.302-2delA variant occurs in the invariant region (+/- 1,2) of the splice con sensus sequence and is predicted to cause altered splicing leading to an abnorma l or absent protein. In vitro studies as well as sequencing of cDNA from individ uals with this variant showed that it leads to activation of a cryptic splice si te, leading to 10 bp frameshift at the beginning of the next exon and resulting in the addition of 14 new amino acid residues and a premature stop codon (Chen 2 006). In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer (HBOC) in an autosomal dominant manner bas ed upon presence in multiple affected individuals, segregation studies, absence from the general population, functional evidence, and predicted impact on the pr otein. ACMG/AMP Criteria applied (Richards 2015): PVS1, PS4, PP1_Strong.
Color Diagnostics, LLC DBA Color Health	RCV000130037	SCV001340640	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-28	criteria provided, single submitter	clinical testing	This variant causes deletion of the nucleotide at the -2 position of intron 5 of the BRCA1 gene. RNA studies found the variant to activate a cryptic splice acceptor site leading to a 10bp frameshift, premature truncation, and nonsense-mediated decay (PMID: 12815598, 16619214). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 9333265, 10486320, 12815598, 16211554, 16619214, 20104584) and has been identified in 22 families among CIMBA participants (PMID: 29446198). In one large pedigree, this variant was found to segregate with breast cancer, ovarian cancer, and melanoma in at least 9 affected individuals (PMID: 12815598). This variant has not been identified 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 Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048047	SCV001360564	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.302-2delA 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. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a canonical 3 acceptor site and two predict it creates/strengthens a cryptic exonic 3 acceptor site. These predictions are supported by analysis of cDNA products demonstrating that the variant activates a cryptic splicing site which results in a 10-bp frameshift deletion at the beginning of exon 6 causing the addition of 14 new residues and resulting in a premature stop codon (Chen_2006). c.302-2delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Tesoriero_2005, Borg_2010, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077534	SCV000109335	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077534	SCV000144967	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048047	SCV000587044	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735535	SCV000863673	pathogenic	Breast and/or ovarian cancer	2011-08-22	no assertion criteria provided	clinical testing