Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_007294.4(BRCA1):c.593+4delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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: Uncertain_significance. The variant received 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
NM_007294.4
MANE Select
c.593+4delA
splice_region intron
N/A
NP_009225.1
BRCA1
NM_001407581.1
c.593+4delA
splice_region intron
N/A
NP_001394510.1
BRCA1
NM_001407582.1
c.593+4delA
splice_region intron
N/A
NP_001394511.1
Ensembl Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
ENST00000357654.9
TSL:1 MANE Select
c.593+4delA
splice_region intron
N/A
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.593+4delA
splice_region intron
N/A
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.593+4delA
splice_region intron
N/A
ENSP00000419274.2
Frequencies
GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:1
Nov 27, 2023
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group SUncertain:1
Feb 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
not providedUncertain:1
May 01, 2020
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on splicing; Also known as 712+4delG
The c.593+4delA intronic variant, located in intron 7 of the BRCA1 gene, results from a deletion of one nucleotide within intron 7 of the BRCA1 gene. 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; however, this alteration occurs at a splice junction that is located at a naturally occurring, alternatively spliced exon and, thus, the effects of abnormal splicing cannot be predicted (Ambry internal data; Colombo M et al. Hum. Mol. Genet., 2014 Jul;23:3666-80). Based on the available evidence, the clinical significance of this alteration remains unclear.
Hereditary breast ovarian cancer syndromeUncertain:1
Feb 01, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
ClinVar contains an entry for this variant (Variation ID: 531202). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This sequence change falls in intron 8 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. It affects a nucleotide within the consensus splice site. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.