Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.83_84delTG(p.Leu28ArgfsTer12) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L28L) has been classified as Likely benign.
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 3630 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43115775-CCA-C is Pathogenic according to our data. Variant chr17-43115775-CCA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 55733.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.83_84delTG
p.Leu28ArgfsTer12
frameshift splice_region
Exon 3 of 23
NP_009225.1
BRCA1
NM_001407581.1
c.83_84delTG
p.Leu28ArgfsTer12
frameshift splice_region
Exon 3 of 24
NP_001394510.1
BRCA1
NM_001407582.1
c.83_84delTG
p.Leu28ArgfsTer12
frameshift splice_region
Exon 3 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.83_84delTG
p.Leu28ArgfsTer12
frameshift splice_region
Exon 3 of 23
ENSP00000350283.3
BRCA1
ENST00000471181.7
TSL:1
c.83_84delTG
p.Leu28ArgfsTer12
frameshift splice_region
Exon 3 of 24
ENSP00000418960.2
BRCA1
ENST00000470026.6
TSL:1
c.83_84delTG
p.Leu28ArgfsTer12
frameshift splice_region
Exon 3 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:5
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)
Significance:Pathogenic
Review Status:criteria provided, single submitter
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.
Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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
Apr 02, 2018
Counsyl
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Hereditary breast ovarian cancer syndromePathogenic:2
Mar 24, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BRCA1 c.83_84delTG (p.Leu28ArgfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250508 control chromosomes (gnomAD). c.83_84delTG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer (example: Gaceb_2018 and Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Five submitters (including an expert panel - ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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.Leu28Argfs*12) 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: 18645608, 20104584, 22684231). ClinVar contains an entry for this variant (Variation ID: 55733). For these reasons, this variant has been classified as Pathogenic.
The c.83_84delTG pathogenic mutation, located in coding exon 2 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 83 to 84, causing a translational frameshift with a predicted alternate stop codon (p.L28Rfs*12). This alteration has been reported in multiple Algerian families diagnosed with hereditary breast and/or ovarian cancer syndrome (HBOC) (Uhrhammer N et al. Int J Med Sci. 2008; 5(4):197-202; Cherbal F et al. Dis. Markers. 2010; 28(6):377-84). In addition to the clinical data presented in the literature, 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.