Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3169_3172delAGTA(p.Ser1057LeufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S1057S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
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
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43092358-ATACT-A is Pathogenic according to our data. Variant chr17-43092358-ATACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 54788.Status of the report is reviewed_by_expert_panel, 3 stars.
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.3169_3172delAGTA
p.Ser1057LeufsTer4
frameshift
Exon 10 of 23
NP_009225.1
BRCA1
NM_001407581.1
c.3169_3172delAGTA
p.Ser1057LeufsTer4
frameshift
Exon 10 of 24
NP_001394510.1
BRCA1
NM_001407582.1
c.3169_3172delAGTA
p.Ser1057LeufsTer4
frameshift
Exon 10 of 24
NP_001394511.1
Ensembl Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
BRCA1
ENST00000357654.9
TSL:1 MANE Select
c.3169_3172delAGTA
p.Ser1057LeufsTer4
frameshift
Exon 10 of 23
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.3169_3172delAGTA
p.Ser1057LeufsTer4
frameshift
Exon 10 of 24
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.3169_3172delAGTA
p.Ser1057LeufsTer4
frameshift
Exon 10 of 23
ENSP00000419274.2
Frequencies
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:1
Dec 15, 2017
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
Variant allele predicted to encode a truncated non-functional protein.
Hereditary breast ovarian cancer syndromePathogenic:1
Jan 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change creates a premature translational stop signal (p.Ser1057Leufs*4) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 22486713, 35710434). ClinVar contains an entry for this variant (Variation ID: 54788). For these reasons, this variant has been classified as Pathogenic.
Familial cancer of breastOther:1
ClinVar Staff, National Center for Biotechnology Information (NCBI)