Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.441+2T>A variant causes a splice donor, 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 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43104120-A-T is Pathogenic according to our data. Variant chr17-43104120-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Hereditary breast ovarian cancer syndrome Pathogenic:3
Apr 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change affects a donor splice site in intron 6 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 hereditary breast and/or ovarian cancer (PMID: 21769658, 28651617, 29907814). ClinVar contains an entry for this variant (Variation ID: 55196). 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: 21769658). Studies have shown that disruption of this splice site results in use of cryptic donor and acceptor splice sites and introduces a premature termination codon (PMID: 21769658). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Nov 01, 2021
Genetics Program, Instituto Nacional de Cancer
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research
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Jul 02, 2018
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.441+2T>A intronic variant results from a T to A substitution two nucleotides after coding exon 5 in the BRCA1 gene. This alteration has been observed in a cohort of Brazilian patients tested for BRCA1/2 mutations (Palmero EI et al. Sci Rep, 2018 06;8:9188). This alteration was tested by RT-PCR and shown to result in a transcript that uses an alternate donor site within coding exon 5 leading to a predicted frameshift with premature termination codon (Thomassen M et al. Breast Cancer Res. Treat., 2012 Apr;132:1009-23). A close match alteration, c.441+2T>G was also shown to induce the same aberrant transcript (Colombo M et al. PLoS ONE, 2013 Feb;8:e57173). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Jan 31, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant causes a T to A nucleotide substitution at the +2 position of intron 6 of the BRCA1 gene. This variant is also known as 560+2T>A or IVS7+2T>A based on Breast Cancer Information Core (BIC) nomenclature. Functional RNA studies have shown that this variant causes the activation of a cryptic splice site in exon 7, resulting in a frameshift deletion and premature truncation in exon 7 (PMID: 21769658, 24884479). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21769658, 23469205, 24884479), and in individuals at high risk for hereditary breast and ovarian cancer (PMID: 29907814). 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. -
Breast and/or ovarian cancer Pathogenic:1
May 29, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Dec 16, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter