Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5075-1G>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 Likely 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 0.013769671 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.4, offset of 42, new splice context is: gacactgaaatattttctAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43063952-C-T is Pathogenic according to our data. Variant chr17-43063952-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063952-C-T is described in Lovd as [Pathogenic]. Variant chr17-43063952-C-T is described in Lovd as [Pathogenic].
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Jan 31, 2014
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Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Nov 29, 2023
This sequence change affects an acceptor splice site in intron 16 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 12402332, 27433846, 29566657). This variant is also known as IVS17-1G>A. ClinVar contains an entry for this variant (Variation ID: 55377). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24667779). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Aug 01, 2020
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Jun 25, 2018
This variant is denoted BRCA1 c.5075-1G>A or IVS16-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 16 of the BRCA1 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also known as BRCA1 5194-1G>A and IVS17-1G>A using alternate nomenclature, has been reported in individuals suspected of having hereditary breast/ovarian cancer as well as in at least one individual with metastatic prostate cancer (Jara 2006, Pritchard 2016, Apessos 2018, Wang 2018). We consider this variant to be pathogenic. -
The c.5075-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 16 of the BRCA1 gene. This alteration has been reported in individuals of various ethnic backgrounds with personal and/or family history of breast, ovarian, and/or prostate cancer (Frank TS et al. J. Clin. Oncol., 2002 Mar;20:1480-90; Jara L et al. Cancer Genet. Cytogenet., 2006 Apr;166:36-45; Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53; Apessos A et al. Cancer Genet, 2018 01;220:1-12; Wang YA et al. BMC Cancer, 2018 03;18:315; Machackova E et al. Klin Onkol, 2019;32:51-71). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this alteration is also designated as IVS17-1G>A in published literature. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. A close match alteration, BRCA1 c.5075-2A>G causes aberrant coding exon 16 skipping (called exon 18 in some literature-Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38; Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the majority of available evidence to date, this variant is classified as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Nov 09, 2021
This variant causes a G to A nucleotide substitution at the -1 position of intron 16 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional study has reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been detected in three individuals affected with breast cancer (PMID: 16616110; Color internal data) and additional families suspected of hereditary breast and ovarian cancer (PMID: 12402332, 29310832, 29566657). Other canonical splice acceptor site variants in intron 16 have been reported as disease-causing in ClinVar (variation ID 55378, 55379, 55380, 125759, 252381) and reported in individuals or families affected with breast or ovarian cancer (PMID: 29446198, 30287823). 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 Likely Pathogenic. -
Breast neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitter
research
Yang An-Suei Laboratory, Academia Sinica
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Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneKor MSA
Jan 01, 2020
This variant is a substitution of the last nucleotide of intron 17 of the BRCA gene. This particular position is highly conserved in human as well as in other genomes. It is expected that this variant affects the correct mRNA splicing and results in the deletion of an entire exon. This causes the formation of a truncated non functional protein. This mutation has been described in breast cancer patients (PMID: 16616110). This particular variant has been described in the mutation database ClinVar (Variation ID: 55377/) -