Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.1561_1564delGCAGinsTAAA(p.AlaAsp521*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A521A) 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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 17-43093967-CTGC-TTTA is Pathogenic according to our data. Variant chr17-43093967-CTGC-TTTA is described in ClinVar as Pathogenic. ClinVar VariationId is 54292.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.1561_1564delGCAGinsTAAA
p.AlaAsp521*
stop_gained
N/A
NP_009225.1
BRCA1
NM_001407581.1
c.1561_1564delGCAGinsTAAA
p.AlaAsp521*
stop_gained
N/A
NP_001394510.1
BRCA1
NM_001407582.1
c.1561_1564delGCAGinsTAAA
p.AlaAsp521*
stop_gained
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.1561_1564delGCAGinsTAAA
p.AlaAsp521*
stop_gained
N/A
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.1561_1564delGCAGinsTAAA
p.AlaAsp521*
stop_gained
N/A
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.1561_1564delGCAGinsTAAA
p.AlaAsp521*
stop_gained
N/A
ENSP00000419274.2
Frequencies
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
This variant changes 4 nucleotides in exon 10 of the BRCA1 gene, c.1561_1564delGCAGinsTAAA, creating a premature translation stop signal at codon 521. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with cancer of the fallopian tube with a family history of breast cancer (PMID: 12030901). 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.
Hereditary breast ovarian cancer syndromePathogenic:1
Sep 17, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with fallopian tube cancer and/or hereditary breast and ovarian cancer (PMID: 12030901, 28056804). ClinVar contains an entry for this variant (Variation ID: 54292). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Ala521*) 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).