The BRCA1 c.135-1G>T (NP_009225.1:p.?) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar with a pathogenic expert-panel classification.1 This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 7.14e-06 (2/280296 alleles) and gnomAD v4.1 AF 4.42e-06 (7/1583254 alleles), which is below benign frequency thresholds but does not meet the ENIGMA PM2 requirement for absence from controls.2 RNA and multifactorial evidence support a damaging splice effect for this variant, including exon 5 deletion in splicing studies, ENIGMA assignment of PVS1 (RNA), a reference-set posterior probability of 0.99999838416, and a BRCA1 clinical-history likelihood ratio of 59.69 across 7 probands, supporting PP4_Strong.3 In silico splicing analysis predicts a strong splice effect, with a SpliceAI maximum delta score of 0.86, which is consistent with disruption of normal splicing but is not counted separately as PP3 because the same splice evidence is already captured under the PVS1 framework.4
Final classification
Pathogenic
PVS1PP4PP5
BRCA1
c.135-1G>T
p.?
This variant
The BRCA1 c.135-1G>T (NP_009225.1:p.?) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar with a pathogenic expert-panel classification.
ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules from final_classification_framework).
Classification rationale
PVS1PP4PP5
Pathogenic
BRCA1 c.135-1G>T
PVS1 + PP4 + PP5
→
Pathogenic
3
vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001vcep_pmid_31853058_brca1_clinical_history_lrPMID:20020529 ↗PMID:31853058 ↗
4
spliceai ↗pvs1_variant_assessmentcspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 10 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
review
Pathogenic
This BRCA1 variant affects the canonical splice acceptor at c.135-1. BRCA1 loss of function is an established disease mechanism, but the ENIGMA BRCA1 exon-specific table assigns c.135-1G>T to PVS1 (RNA) rather than full-strength generic PVS1 because available RNA data show aberrant splicing with exon 5 deletion, consistent with a damaging loss-of-function effect.
Canonical acceptor variant at -1 positionBRCA1 loss of function eligible for PVS1ENIGMA Table 4 row for c.135-1G>T assigns PVS1 (RNA)
PP4
strong
Pathogenic
Variant-specific clinical-history likelihood-ratio evidence supports pathogenicity. In the BRCA1 clinical-history LR table, this variant has LR 59.69 in 7 probands, which is above the ENIGMA PP4_Strong threshold of 18.7.
Clinical-history LR 59.68716765674412N probands 7PP4_Strong threshold 18.7
Assessed · not applied
· 4 not met · 6 not assessed
Pathogenic
PS1
Available evidence does not establish, within the retrieved materials, that this variant should receive PS1 based on a previously classified variant with the same proven splicing consequence at the weight required by the ENIGMA BRCA1 rules.
PS4
This variant has been reported in affected individuals, but no ethnicity-matched case-control analysis with p-value less than or equal to 0.05 and odds ratio at least 4, with the lower confidence interval excluding 2.0, was identified from the retrieved evidence.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified for co-occurrence with another BRCA1 variant in a proband with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 cannot be assessed from the available data.
PP1
No quantitative co-segregation likelihood ratio meeting ENIGMA PP1 thresholds was identified in the available evidence, so co-segregation support cannot be assigned.
Benign
BA1
Population frequency does not meet the benign stand-alone threshold.
BS1
Population frequency does not meet the benign strong or supporting thresholds.
BS2
No point-based evidence from unaffected individuals or from individuals lacking features of BRCA1-related Fanconi anemia was identified, so BS2 cannot be assessed from the available data.
BS4
No quantitative lack-of-segregation likelihood ratio meeting ENIGMA BS4 thresholds was identified in the available evidence, so BS4 cannot be assigned.
BP5
Variant-specific clinical-history evidence does not support BP5.
N/A · 15
PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · BS3 · BP1 · BP2 · BP3 · 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= 4.42127e-06; MAF= 0.00044%, 7/1583254 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.06741e-06; MAF= 0.00061%, 7/1153704 alleles, homozygotes = 0); grpmax FAF= 2.52e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.13531e-06; MAF= 0.00071%, 2/280296 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56177e-05; MAF= 0.00156%, 2/128060 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00044%
· 7 / 1,583,254
0 hom · FAF 0.00025%
0 hom · FAF 0.00025%
European (non-Finnish) 7 / 1,153,704 |
0.00061% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00071%
· 2 / 280,296
0 hom
0 hom
European (non-Finnish) 2 / 128,060 |
0.0016% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (17 clinical laboratories) and as pathogenic (1 clinical laboratory) and as not provided (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.86).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV100524937, n = 1 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Bayes analysis provides evidence of pathogenicity for the BRCA1 c.135-1G>T (I
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
very strong
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→PP4
strong
Sources & reference links