NM_007294.4:c.2182A>T (p.Arg728Ter) is a nonsense variant in BRCA1 exon 10 (legacy exon 11), predicted to undergo nonsense-mediated decay (>1900 nt upstream of the terminal exon junction).1 Per ENIGMA Specification Table 4, BRCA1 exon 10 PTC variants are assigned PVS1 (Very Strong) weight. Loss of function is an established disease mechanism for BRCA1.2 ENIGMA Specification Table 4 assigns PM5_Strong (PTC) for nonsense variants in BRCA1 exon 10, where multiple proven pathogenic PTC variants have been observed. This is supported by ≥4 evidence points across functional assay, case-control, personal/family history, and CIMBA data (Supplementary Table 1).3 The variant is absent from gnomAD v2.1 (non-cancer, exome only), gnomAD v4.1 (non-cancer), and gnomAD-Canada v1.0, meeting ENIGMA PM2_Supporting.4 ENIGMA point-based combining rules (Table 3): PVS1 Very Strong (8 points) + PM5 Strong (4 points) + PM2 Supporting (1 point) = 13 points, meeting the Pathogenic threshold (≥10 points).5
BRCA1
Final classification
Pathogenic
BRCA1 c.2182A>T · p.Arg728Ter
BRCA1
NM_007294.4:c.2182A>T (p.Arg728Ter) is a nonsense variant in BRCA1 exon 10 (legacy exon 11), predicted to undergo nonsense-mediated decay (>1900 nt upstream of the terminal exon junction).
ENIGMA BRCA1/2 VCEP point system (Table 3): PVS1 Very Strong (8 points) + PM5 Strong (4 points) + PM2 Supporting (1 point) = 13 points, exceeding the Pathogenic threshold (≥10). Also satisfies the categorical rule: 1 Very Strong (PVS1) + ≥1 Strong (PM5) → Pathogenic.
Classification rationale
PVS1PM2PM5
Pathogenic
BRCA1 c.2182A>T
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 applied · 8 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
Nonsense variant NM_007294.4:c.2182A>T (p.Arg728Ter) in BRCA1 exon 10 (legacy exon 11). BRCA1 loss of function is an established disease mechanism. The PTC occurs at codon 728 within the large exon 10 (c.671-4096, codons 224-1366), located >1900 nt upstream of the exon 10-11 junction, predicting nonsense-mediated decay. Per ENIGMA Specification Table 4, BRCA1 exon 10 PTC variants are assigned PVS1 at full (Very Strong) weight.
ENIGMA Table 4: BRCA1 exon 10 (legacy E11) PTC → PVS1Nonsense variant p.Arg728Ter in exon 10NMD predicted (>1900 nt upstream of terminal junction)
✓
PM2
supporting
Pathogenic
Absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Per ENIGMA specification, absence from outbred population controls in gnomAD qualifies for PM2_Supporting.
gnomAD v2.1: absentgnomAD v4.1: absentgnomAD-Canada v1.0: absent
✓
PM5
strong
Pathogenic
ENIGMA Specification Table 4 assigns PM5_Strong (PTC) for nonsense variants in BRCA1 exon 10 (legacy exon 11). This exon has multiple proven pathogenic PTC variants, and the PM5_PTC code is supported by sufficient evidence across functional assay, case-control, personal/family history, and CIMBA data per Supplementary Table 1.
ENIGMA Table 4: BRCA1 exon 10 PTC → PM5_Strong (PTC)ENIGMA ST1: BRCA1 exon 10 PM5_PTC code = Strong≥4 points across evidence types
Assessed · not applied
Pathogenic
PS4
ENIGMA PS4 requires a case-control study with p-value ≤ 0.05 and OR ≥ 4 (lower CI excludes 2.0).
PP1
ENIGMA PP1 requires quantitative co-segregation analysis yielding an LR ≥ 2.08 (Supporting).
PP4
ENIGMA PP4 requires a clinical-history likelihood ratio ≥ 2.08 (Supporting) from multifactorial likelihood clinical data.
Benign
BA1
ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% in gnomAD v2.1 non-cancer exome or v3.1 non-cancer, non-founder populations.
BS1
ENIGMA BS1 requires FAF > 0.01% (Strong) or FAF > 0.002% and ≤ 0.01% (Supporting) in gnomAD non-cancer subsets.
BS2
ENIGMA BS2 requires absence of Fanconi Anemia phenotype features and ≥ 4 points under the Specification Table 8 scoring system.
BS4
ENIGMA BS4 requires quantitative co-segregation analysis showing lack of segregation in affected family members (LR ≤ 0.48 for Supporting).
BP5
ENIGMA BP5 requires a clinical-history LR ≤ 0.48 (Supporting) from multifactorial likelihood data.
N/A · 17
PS1 · PS2 · PS3 · PM1 · PM3 · PM4 · PM6 · PP2 · PP3 · PP5 · BS3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 2811747)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.179714.
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.
Sources & reference links
9Sources
Triaged references · 9 PMIDs not cited in assessment
12947386 ↗
Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.
ONCOKB
20608970 ↗
BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.
ONCOKB
20104584 ↗
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
CLINVAR
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR