NM_007294.4:c.4689C>G (p.Tyr1563Ter) is a nonsense variant in BRCA1 exon 15(16) that creates a premature termination codon. PVS1 is met at Very Strong strength: loss-of-function is an established disease mechanism for BRCA1, and the ENIGMA Table 4 PVS1 decision framework assigns full-strength PVS1 to protein termination codon variants in exon 15(16). Nonsense-mediated decay is predicted as the PTC at codon 1563 is upstream of the annotated NMD escape boundary.1 PM5_Strong (PTC) is met: ENIGMA Table 4 assigns PM5_Strong for PTC variants in exon 15(16), supported by 15 total evidence points in Supplementary Table ST1 spanning functional assay data, clinical history, and population-level evidence.2 PP4_Strong is met: the clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 159.82 (17 probands), greatly exceeding the ENIGMA PP4_Strong threshold of LR ≥ 18.7. The variant's personal and family cancer history is highly consistent with known pathogenic BRCA1 variants.3 PM2 is not met: the variant is observed at extremely low frequency in gnomAD (v2.1: 1/250,704; v4.1: 5/1,614,030). Under ENIGMA, a single observation in an outbred population is not considered informative for PM2 assignment.4 PS3 is not met: no variant-specific functional assay data exist for c.4689C>G in the ENIGMA Table 9 curated functional assay results or in the reviewed literature.5 No benign criteria are met. The population frequencies are far below BS1 and BA1 thresholds, no functional data support BS3, and the clinical history LR is in the pathogenic direction.6 Combined classification: PVS1 (Very Strong) + PM5_Strong (Strong) + PP4_Strong (Strong) meets ENIGMA Table 3 pathogenic combination rule (≥1 Very Strong + ≥1 Strong).7
BRCA1
Final classification
Pathogenic
BRCA1 c.4689C>G · p.Tyr1563Ter
BRCA1
NM_007294.4:c.4689C>G (p.Tyr1563Ter) is a nonsense variant in BRCA1 exon 15(16) that creates a premature termination codon.
ENIGMA BRCA1/BRCA2 VCEP v1.2 Table 3: ≥1 Very Strong + ≥1 Strong → Pathogenic. PVS1 (Very Strong) + PM5_Strong (Strong) + PP4_Strong (Strong) satisfy this rule. No benign criteria are met. Point-system corroboration: +17 points (≥10 threshold for Pathogenic).
Classification rationale
PVS1PM5PP4PP5
Pathogenic
BRCA1 c.4689C>G
PVS1 + PM5 + PP4 + PP5
→
Pathogenic
1
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
2
cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
3
PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lr
5
vcep_specifications_table9_v1_2_2024_11_18
7
cspec ↗final_classification_framework
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 10 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
Nonsense variant NM_007294.4:c.4689C>G (p.Tyr1563Ter) in BRCA1 exon 15(16), a gene where loss-of-function is an established disease mechanism for hereditary breast and ovarian cancer. ENIGMA Table 4 assigns PVS1 at full strength for protein termination codon variants in exon 15(16). Nonsense-mediated decay is predicted as the premature termination codon is located well upstream of the last exon-exon junction and outside the NMD escape boundary annotated in the ENIGMA specification.
Nonsense variant creating premature termination codon at p.Tyr1563Ter in BRCA1 exon 15(16)ENIGMA Table 4 assigns PVS1 (full strength) for PTC variants in exon 15(16)BRCA1 loss-of-function is an established germline disease mechanism per ClinGen ENIGMA VCEP v1.2
✓
PM5
strong
Pathogenic
ENIGMA Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA1 exon 15(16). This exon is not among the PM5_N/A exons (E21(22), E6(7), E7(8)). Supplementary Table ST1 confirms PM5_Strong with 15 total evidence points: functional assay PTC loss-of-function (4 points), functional assay missense loss-of-function (2 points), personal and family history LR (4 points), standardised incidence ratio (4 points), and CIMBA (1 point). Multiple proven pathogenic PTC variants have been observed in this exon.
ENIGMA Table 4: PM5_Strong (PTC) assigned to exon 15(16)ENIGMA ST1: 15 total evidence points across 5 categories support PM5_Strong for exon 15(16)4 functional assay studies confirm PTC loss-of-function in exon 15(16)
✓
PP4
strong
Pathogenic
Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio for c.4689C>G is 159.82 (LOG(LR)=5.074, N=17 probands), exceeding the ENIGMA PP4_Strong threshold of LR ≥ 18.7. The variant's personal and family cancer history profile is highly consistent with that observed for known pathogenic BRCA1 variants.
Clinical-history LR = 159.82 (Li et al. 2020PMID:31853058)N = 17 probands
Assessed · not applied
Pathogenic
PS3
ENIGMA Table 9 contains no pre-assigned PS3 code for c.4689C>G, and no variant-specific functional data were identified in the literature.
PS4
No case-control study satisfying ENIGMA PS4 requirements (p ≤ 0.05, OR ≥ 4, lower confidence interval excludes 2.0, ethnicity- and country-matched controls) was identified for c.4689C>G in the case materials.
PM2
ENIGMA PM2_Supporting requires absence from gnomAD controls in outbred populations.
PP1
No quantitative co-segregation analysis data meeting ENIGMA PP1 thresholds (LR ≥ 2.08 by Bayes score) was available for c.4689C>G in the case materials.
Benign
BA1
ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% in gnomAD v2.1 or v3.1 non-founder populations.
BS1
ENIGMA BS1_Supporting requires FAF > 0.002% in gnomAD non-founder populations; BS1_Strong requires FAF > 0.01%.
BS2
No individual-level co-occurrence data with Fanconi Anemia phenotype or healthy adult observation meeting ENIGMA Table 8 criteria was available for c.4689C>G in the case materials.
BS3
ENIGMA Table 9 contains no pre-assigned BS3 code for c.4689C>G.
BS4
No quantitative co-segregation analysis data showing lack of segregation meeting ENIGMA BS4 thresholds was available for c.4689C>G in the case materials.
BP5
The Li et al.
N/A · 11
PS1 · PS2 · PM1 · PM6 · PP2 · PP3 · BP1 · BP2 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.09784e-06; MAF= 0.00031%, 5/1614030 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23728e-06; MAF= 0.00042%, 5/1180002 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98877e-06; MAF= 0.00040%, 1/250704 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83798e-06; MAF= 0.00088%, 1/113148 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,614,030
0 hom · FAF 0.00012%
0 hom · FAF 0.00012%
European (non-Finnish) 5 / 1,180,002 |
0.00042% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 250,704
0 hom
0 hom
European (non-Finnish) 1 / 113,148 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (39 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 37607)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.280476.
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 · 8 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
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR