Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.441+1G>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]
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, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43104121-C-T is Pathogenic according to our data. Variant chr17-43104121-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:2
May 05, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
A known pathogenic mutation in the BRCA1 gene was detected in this specimen. This sequence change affects a donor splice site in intron 6 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not gnomAD. This variant has been observed in individuals with breast cancer (PMID: 16619214, 29752822, 20104584). ClinVar contains an entry for this variant (Variation ID: 55195) with 4 submitters all of which describe the variant as pathogenic, no conflicts. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16619214). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as pathogenic. This variant has been confirmed by sanger sequencing. -
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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not providedPathogenic:2
Aug 09, 2023
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Canonical splice site variant demonstrated to result in out-of-frame exon skipping, which is predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Steffensen et al., 2014); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Chen et al., 2006; Lilyquist et al., 2017; Li et al., 2019; Ashour and Shafik 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 560+1G>A and IVS7+1G>A; This variant is associated with the following publications: (PMID: 25525159, 20104584, 26247049, 23348723, 29446198, 29752822, 24667779, 31372034, 16619214, 28888541) -
Mar 21, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The BRCA1 c.441+1G>A variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. This variant has been reported in the published literature in individuals with a personal and family history of breast and/or ovarian cancer (PMIDs: 29752822 (2018), 16619214 (2006)). 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. -
This variant causes a G to A nucleotide substitution at the +1 position of intron 6 of the BRCA1 gene. RNA studies have reported that this variant causes the out-of-frame deletion of 62 nucleotides from exon 6 that is expected to produce an absent or nonfunctional protein product (PMID: 16619214, 24667779). This variant has been reported in several individuals affected with breast and ovarian cancer (PMID: 16455195, 16619214, 31372034). 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 06, 2016
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.441+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the BRCA1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. This alteration has been identified in a high-risk breast and ovarian cancer family and associated with aberrant splicing by RT-PCR analysis (Chen X et al, Hum. Mutat. 2006 May; 27(5):427-35). Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.441+1G>A variant is classified as likely pathogenic. -
Hereditary breast ovarian cancer syndromePathogenic:1
Jan 28, 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 breast and/or ovarian cancer (PMID: 16619214, 29752822, 31372034). ClinVar contains an entry for this variant (Variation ID: 55195). Studies have shown that disruption of this splice site results in a 62-bp deletion at the end of exon 7 and introduces a premature termination codon (PMID: 16619214). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -