Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3365_3366delCA(p.Thr1122ArgfsTer10) 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. T1122T) 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 17-43092164-CTG-C is Pathogenic according to our data. Variant chr17-43092164-CTG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 54859.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.3365_3366delCA
p.Thr1122ArgfsTer10
frameshift
Exon 10 of 23
NP_009225.1
BRCA1
NM_001407581.1
c.3365_3366delCA
p.Thr1122ArgfsTer10
frameshift
Exon 10 of 24
NP_001394510.1
BRCA1
NM_001407582.1
c.3365_3366delCA
p.Thr1122ArgfsTer10
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.3365_3366delCA
p.Thr1122ArgfsTer10
frameshift
Exon 10 of 23
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.3365_3366delCA
p.Thr1122ArgfsTer10
frameshift
Exon 10 of 24
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.3365_3366delCA
p.Thr1122ArgfsTer10
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:4
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
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
Sep 08, 2016
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.
Jul 19, 2023
All of Us Research Program, National Institutes of Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast cancer (PMID: 27469594). 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:2
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research
Apr 30, 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.Thr1122Argfs*10) 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: 27469594). This variant is also known as 3484delCA. ClinVar contains an entry for this variant (Variation ID: 54859). For these reasons, this variant has been classified as Pathogenic.
not providedPathogenic:1
Dec 30, 2015
Quest Diagnostics Nichols Institute San Juan Capistrano
The c.3365_3366delCA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3365 to 3366, causing a translational frameshift with a predicted alternate stop codon (p.T1122Rfs*10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.