Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.302-2A>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 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3, offset of 10, new splice context is: tattttaccgatgcaaacAGcta. 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 17-43104263-T-G is Pathogenic according to our data. Variant chr17-43104263-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:4
Aug 14, 2009
Sharing Clinical Reports Project (SCRP)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Nov 25, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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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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Aug 01, 2020
Kong lab, Department of Laboratory Medicine, National Cancer Center
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research
The c.302-2A>C variant in BRCA1 was detected in a patient, who was diagnosed with breast cancer (invasive ductal carcinoma, IDC), HR+, HER2- at 46 years of age. RT-PCR and Sanger sequencing analyses demonstrated that this variant caused partial exon 7 deletion, resulting in a truncated BRCA1 protein (Ryu et al., 2020; PMID: 32761968). This variant is absent from population databases, including ExAC and gnomAD. Given its impact on exon splicing and protein truncation, BRCA1 c.302-2A>C has been classified as pathogenic. -
This variant causes an A to C nucleotide substitution at the -2 position of intron 5 of the BRCA1 gene. RNA studies using patient-derived lymphocytes have shown that this variant causes a 10bp deletion in exon 7, leading to premature truncation and nonsense-mediated decay (PMID: 32761968). This variant has been reported in individuals affected with breast cancer or ovarian cancer (PMID: 22798144, 30309222, 31924417, 32455662, 32761968, 33471991; Kwon et al, 2021, DOI: 10.21203/rs.3.rs-734551/v1) and has been identified in 4 families among CIMBA participants (PMID: 29446198). 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. -
Jun 13, 2023
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.302-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 5 in the BRCA1 gene. This variant has been reported in multiple individuals with a history of breast cancer (Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Park JS et al. Cancer Res Treat. 2017 Oct;49:1012-1021; Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620; Bang YJ et al. Cancer Res Treat. 2022 Jul;54(3):827-833). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 and will 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 likely pathogenic. -
Gastric cancerPathogenic:1
Jul 01, 2021
Laboratory for Genotyping Development, RIKEN
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research
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not providedPathogenic:1
Jun 22, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA1 mRNA splicing. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 28111427 (2017), 25863477 (2015), 22798144 (2012), 33471991 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Hereditary breast ovarian cancer syndromePathogenic:1
Apr 27, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 18712473, 31343793; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that disruption of this splice site alters BRCA1 gene expression (PMID: 31343793). ClinVar contains an entry for this variant (Variation ID: 37500). Disruption of this splice site has been observed in individual(s) with a personal and/or family history of breast cancer and ovarian cancer (PMID: 22798144, 28111427, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 5 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. -