NM_007294.4:c.2657_2676del is a 20bp frameshift deletion in BRCA1 exon 10(11) that creates a premature termination codon at p.Ser886Ter. BRCA1 loss of function is an established mechanism for hereditary breast and ovarian cancer.1 Per ENIGMA BRCA1 VCEP Specifications Table 4, PTC variants in exon E10(11) are assigned PVS1 (Very Strong) as null variants in a gene where loss of function is a known disease mechanism, and PM5_Strong (PTC) because other proven pathogenic PTC variants have been reported in this exon.2 The variant is absent from gnomAD v2.1 and v4.1 population databases (allele count = 0), meeting PM2 at Supporting strength per ENIGMA population frequency rules.3 Applying the ENIGMA Table 3 point system: PVS1 Very Strong = 8 points, PM5 Strong = 4 points, PM2 Supporting = 1 point. Total = 13 points, which falls in the Pathogenic range (>=10).4
BRCA1
Final classification
Pathogenic
BRCA1 c.2657_2676del · p.Ser886Ter
BRCA1
NM_007294.4:c.2657_2676del is a 20bp frameshift deletion in BRCA1 exon 10(11) that creates a premature termination codon at p.Ser886Ter. BRCA1 loss of function is an established mechanism for hereditary breast and ovarian cancer.
ENIGMA BRCA1 VCEP Specification v1.2.0 Table 3. No conflicting evidence: no benign criteria are met. Pathogenic criteria: PVS1 (Very Strong, 8 pts) + PM5 (Strong, 4 pts) + PM2 (Supporting, 1 pt). Table 3 pathogenic all_of rule satisfied: 1 Very Strong + >=1 Strong -> Pathogenic. ENIGMA point system confirms: 8+4+1 = 13, in Pathogenic range (>=10).
Classification rationale
PVS1PM2PM5
Pathogenic
BRCA1 c.2657_2676del
PVS1 + PM2 + PM5
→
Pathogenic
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
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—
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Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
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Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 4 PMIDs triaged · 4 high-priority
4papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
11358863 ↗
functional
Tumorigenesis in mice carrying a truncating Brca1 mutation.
We generated mouse mutants carrying in the Brca1 locus a modification (Brca1(tr)) that eliminates the C-terminal half of the protein product and obtained results indicating that, depending on genetic background, the missing BRCT and/or other domains are dispensable for survival, but essential for tumor suppression. Most of the apparently hypomorphic Brca1(tr/tr) mutants developed various tumors. L
BS3PM1PS3
12483515 ↗
functional
The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans.
BRCA1 and BRCA2 mutations are estimated to be responsible for the great majority of familial breast and ovarian cancers. Much progress has been made toward the understanding of the function of these proteins through genetic, biochemical, and structural studies. The embryonic lethality encountered in the knockout mouse initially hindered the development of mouse models aimed at studying tumor suppr
BS3PM1PS3
12947386 ↗
functional
Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.
Inheritance of one defective copy of either of the two breast cancer susceptibility genes, BRCA1 and BRCA2, predisposes individuals to breast and ovarian cancers. Current progress in determining the function of these genes suggests that they participate in a common pathway to facilitate orderly homologous recombination and thereby maintain genomic integrity. As a consequence of this defect in homo
BS3PM1PS3
20608970 ↗
functional
BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.
Mutations in the tumor suppressor breast cancer susceptibility gene 1 (BRCA1), an important player in the DNA damage response, apoptosis, cell cycle regulation and transcription, confer a significantly elevated lifetime risk for breast and ovarian cancer. Although the loss of wild-type BRCA1 function is an important mechanism by which mutations confer increased cancer risk, multiple studies sugges
BS3PM1PS3
Sources & reference links