Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5153-1G>A 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 8.6, offset of 1, new splice context is: ttttctatgatctctttaAGggt. 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-T is Pathogenic according to our data. Variant chr17-43063374-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55429.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063374-C-T is described in Lovd as [Pathogenic]. Variant chr17-43063374-C-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6Other:1
Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Dec 30, 1999
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Pathogenic, criteria provided, single submitter
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Sep 21, 2015
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Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Mar 13, 2023
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Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Jun 18, 2019
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 = 0.991891 -
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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Pathogenic, no assertion criteria provided
clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Oct 17, 2017
This variant is denoted BRCA1 c.5153-1G>A or IVS17-1G>A and consists of a G>A nucleotidesubstitution at the -1 position of intron 17 of the BRCA1 gene. Using alternate nomenclature, this variant haspreviously been published as BRCA1 5272-1G>A. This variant destroys a canonical splice acceptor site and has beenshown to cause abnormal splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNAdecay or to an abnormal protein product (Beristain 2007, Sanz 2010, Steffensen 2014). This variant has beenreported in several breast/ovarian cancer families, and is considered a founder variant in certain Spanish populations(Osorio 2000, de la Hoya 2002, Diez 2003, Infante 2006, Infante 2010, de Juan Jimenez 2013, Hasmad 2015). Basedon the current evidence, we consider this variant to be pathogenic -
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Nov 16, 2018
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Nov 05, 2023
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. 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/or ovarian cancer (PMID: 10755399, 19912264, 20215541, 22460208, 23479189, 27062684). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5272-1G>A. ClinVar contains an entry for this variant (Variation ID: 55429). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20215541, 24667779, 30209399; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
The c.5153-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 17 of the BRCA1 gene. This alteration has been seen in many hereditary breast and ovarian cancer families and is a putative Spanish founder mutation (Infante M et al. Clin. Genet., 2010 Jan;77:60-9; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71). RNA splicing assays have demonstrated aberrant splicing of a single nucleotide deletion resulting in a transcript subject to nonsense-mediated decay (Ambry internal data; Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67; Steffensen AY et al. Eur. J. Hum. Genet., 2014 Dec;22:1362-8). 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. 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. -