Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5153-1G>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 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 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4, offset of -49, new splice context is: ctctctatctccgtgaaaAGagc. Cryptic site results in frameshift 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-C-G is Pathogenic according to our data. Variant chr17-43063374-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 37643.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063374-C-G is described in Lovd as [Pathogenic]. Variant chr17-43063374-C-G is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8Other:1
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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Dec 30, 1999
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Dec 04, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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May 27, 2024
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
PS3; PM2_Supporting; PVS1_Strong (RNA); PP1 -
Aug 26, 2022
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jun 13, 2007
Sharing Clinical Reports Project (SCRP)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Feb 17, 2015
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Aug 10, 2015
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: 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 -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Oct 26, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change affects an acceptor 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. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 18 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134, 27553291). ClinVar contains an entry for this variant (Variation ID: 37643). This variant is also known as 5272-1G>C and IVS18-1G>C. Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 8644702, 11149413, 19912264, 25896959). This variant is not present in population databases (gnomAD no frequency). -
Aug 29, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: The BRCA1 c.5153-1G>C variant involves the alteration of a conserved intronic nucleotide located in a known splice site with 5/5 splice prediction tools predict the loss of a splice site, although these predictions have yet to be functionally assessed. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -
Jun 19, 2020
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.5153-1G>C variant in BRCA1 has been reported in at least 10 individuals with BRCA1-related cancer (first reported by Johannson 1996 PMID: 8644702). It was absent from large population studies. This variant was classified as pathogenic on 08/10/15 by the ClinGen-approved ENIGMA expert panel (Variation ID 37643). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -
not provided Pathogenic:2
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Oct 14, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.5153-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 17 of the BRCA1 gene. This mutation has been previously reported in breast cancer cohorts (Díez O et al. Hum Mutat, 2003 Oct;22:301-12; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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 10;562:217-222). Other alterations impacting the same acceptor site (c.5153-1G>A and c.5153-2delA) have been reported in multiple families of various ethnicities affected with breast and/or ovarian cancer and are both predicted to have a deleterious impact on splicing (Kiechle et al. Hum Mutat. 2000 Dec;16(6):529-30; Sinilnikova OM et al. Fam Cancer. 2006;5(1):15-20; Infante M et al. Clin. Genet., 2010 Jan;77:60-9; Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67; Pern et al. PLoS One. 2012;7(10):e47993; Wappenschmidt et al. PLoS One. 2012;7(12):e50800; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Steffensen AY et al. Eur. J. Hum. Genet., 2014 Dec;22:1362-8; Kang E et al. Breast Cancer REs Treat. 2015 May;151(1):157-68; Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also referred to as 5272-1G>C and IVS18-1G>C in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may 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. -