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
BRCA1
Final classification
Pathogenic
BRCA1 c.135-1G>T · p.?
BRCA1
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 ↗
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
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
PMID PMID:20020529
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
Sources & reference links