Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5153-2delA variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000685 in 1,458,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0073319026 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of -48, new splice context is: ctctctatctccgtgaaaAGagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43063374-CT-C is Pathogenic according to our data. Variant chr17-43063374-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 55431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063374-CT-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Sep 16, 2024
Department of Human Genetics, Hannover Medical School
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Apr 07, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Apr 13, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Aug 10, 2010
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Sep 09, 2022
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:4
Jul 22, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Jan 07, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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 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 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; internal data). For these reasons, this variant has been classified as Pathogenic. -
Jan 27, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -
Review Status: criteria provided, single submitter
Collection Method: 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), an individual affected with ovarian cancer (PMID: 33273034) 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. -
Feb 09, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
May 25, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:1
Sep 06, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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) -
BRCA1-related disorder Pathogenic:1
Mar 20, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: 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. -
Ovarian neoplasm Pathogenic:1
Dec 01, 2018
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne