Submissions for variant NM_007294.4(BRCA1):c.5153-2del

dbSNP: rs273901746

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048829	SCV000076842	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 17 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 11102986, 12393792, 16528604, 23110154, 23239986, 25863477, 28888541). This variant is also known as 5272-2delA and IVS18-2delA. ClinVar contains an entry for this variant (Variation ID: 55431). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 12393792, 23239986, 24667779; Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129629	SCV000184422	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-09	criteria provided, single submitter	clinical testing	The c.5153-2delA intronic pathogenic mutation results from the deletion of one nucleotide at position c.5153-2 and involves the canonical splice acceptor site before coding exon 17 in the BRCA1 gene. This mutation has been reported in multiple families of various ethnicities affected with breast and/or ovarian cancer (Kiechle et al. Hum Mutat. 2000 Dec;16(6):529-30; Sinilnikova OM et al. Fam Cancer. 2006;5(1):15-20; Kang E et al. Breast Cancer REs Treat. 2015 May;151(1):157-68; Rebbeck TR et al. Hum Mutat. 2018 05;39(5):593-620). Other studies have shown that this mutation leads to exon skipping resulting in a premature termination codon (Pern et al. PLoS One. 2012;7(10):e47993; Wappenschmidt et al. PLoS One. 2012;7(12):e50800; Perrin-Vidoz L et al. Hum Mol GEnet. 2002 Nov;11(23):2805-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this mutation is also designated as IVS18-2delA and 5272-2delA 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 interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077603	SCV000326183	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077603	SCV000488462	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000479617	SCV000566340	pathogenic	not provided	2022-09-06	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to cause abnormal splicing resulting in a null allele in a gene for which loss-of-function is a known mechanism of disease (Perrin-Vidoz 2002, Wappenschmidt 2012); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Kiechle 2000, Sinilnikova 2006, Pern 2012, Kang 2015); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5272-2del or IVS18-2del; This variant is associated with the following publications: (PMID: 25863477, 23239986, 16528604, 20104584, 28888541, 12393792, 11102986, 23110154, 26187060, 16685647, 11802209, 17694537, 14760071, 16267036, 30787465)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048829	SCV000605761	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-27	criteria provided, single submitter	clinical testing	The c.5153-2delA variant in BRCA1 has been identified 9 individuals with BCRA1-a ssociated cancers and segregated with disease in 4 affected relatives from 1 fam ily (Kiechle 2000; Breast Cancer Information Core (BIC) database). It was also a bsent from large population studies. This variant is a deletion of one nucleotid e in the invariant region (+/- 1,2) of the splice consensus sequence and is pred icted to cause altered splicing leading to an abnormal or absent protein. In sum mary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer (HBOC) in an autosomal dominant manner.
Color Diagnostics, LLC DBA Color Health	RCV000129629	SCV000683263	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in intron 17 of the BRCA1 gene, disrupting the intron 17 splice acceptor site. This variant is also known as 5272-2delA in the literature. RNA studies have reported that this variant causes the out-of-frame skipping of exon 18, resulting in premature truncation (PMID: 12393792, 23110154). This variant has been reported in at least three individuals affected with breast cancer (PMID: 14760071, 23110154, 25863477, 33471991; Leiden Open Variation Database DB-ID BRCA1_004687) and additional families suspected of hereditary breast and ovarian cancer (PMID: 23239986). 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	RCV000048829	SCV000916812	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5153-2delA 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: Four predict the variant abolishes a 3 acceptor site which is also supported by a functional study (Wappenschmidt_2012). The variant was absent in 250880 control chromosomes (gnomAD). c.5153-2delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Judkins_2005, Grushko_2004, Kiechle_2002, Pern_2012, Perrin-Vidoz_2002, Wappenschmidt_2012, Rebbeck_2018) These data indicate that the variant is very likely to be associated with disease. Eight other ClinVar submitters (evaluation after 2018) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496718	SCV002807611	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000077603	SCV004215162	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-13	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000077603	SCV005044137	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-09-09	criteria provided, single submitter	clinical testing	The c.5153-2del variant (also known as 5272-2delA and IVS18-2delA) in BRCA1 has previously been reported in individuals with Hereditary breast and ovarian cancer (HBOC) [PMID: 11102986, 23110154, 28888541, 30787465] and it has been deposited in ClinVar [ClinVar ID: 55431] as Pathogenic for HBOC by multiple submitters. The c.5153-2del variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases.The c.5153-2del variant in BRCA1 is located in the canonical splice acceptor site of exon 18 of this 22-exon gene. It was demonstrated to result in skipping of exon 18, causing a frameshift and premature incorporation of termination codon (p.Trp1718SerfsTer1) [PMID: 12393792, 23239986]. Other variants affecting the same canonical splice acceptor site have also been reported in the literature in individuals with HBOC [PMID: 32596782]. Based on available evidence this inherited heterozygous c.5153-2del variant identified in BRCA1 is classified as Pathogenic.
Department of Human Genetics, Hannover Medical School	RCV000077603	SCV005324810	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-09-16	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077603	SCV000109406	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-08-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077603	SCV000145355	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	RCV000048829	SCV000587471	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785423	SCV000923995	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004758632	SCV005361030	pathogenic	BRCA1-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The BRCA1 c.5153-2delA variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in multiple individuals with breast cancer (Kiechle et al.. 2000. PubMed ID: 11102986; Pern et al., 2012. PubMed ID: 23110154). This variant has also been referred to as c.5272-2delA or IVS18-2delA in literature. RT-PCR analysis demonstrated that this variant cause exon 19 skipping, which is predicted to lead to a coding frameshift and premature protein truncation (Wappenschmidt et al., 2012. PubMed ID: 23239986). Multiple clinical labs have also interpreted this variant as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/55431/). This variant is interpreted as pathogenic.