The BRCA1 c.5407-10G>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current aggregate classification is Likely Pathogenic with expert-panel review.1 This variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1 (1/251448 alleles; AF 3.98e-06), which is too low for benign population criteria but does not satisfy the BRCA1 ENIGMA requirement for complete absence from gnomAD for PM2.2 In published BRCA1 functional and RNA studies, this variant showed retention of 8 nucleotides from intron 22 and partial functional impact rather than a clearly damaging or clearly benign result, so the ENIGMA BRCA1 functional tables indicate that PS3 and BS3 are not met.3 SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 1.00, which exceeds the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites and supports PP3 at Supporting strength.4
Final classification
Uncertain Significance
PP3PP5
BRCA1
c.5407-10G>A
p.?
This variant
The BRCA1 c.5407-10G>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current aggregate classification is Likely Pathogenic with expert-panel review.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 criteria-combination framework: applied criteria PP3 supporting and PP5 supporting do not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, so the variant is classified as Uncertain Significance.
Classification rationale
PP3PP5
Uncertain Significance
BRCA1 c.5407-10G>A
PP3 + PP5
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗PMID:31143303 ↗
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_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 16 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PP3
supporting
review
Pathogenic
Splice prediction supports an abnormal splicing effect. SpliceAI shows a maximum delta score of 1.00, which is above the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites, so PP3 is met at Supporting strength.
SpliceAI max delta score 1.00.Variant is intronic at c.5407-10outside +/-1
Assessed · not applied
· 8 not met · 8 not assessed
Pathogenic
PVS1
This intronic variant is outside the canonical +/-1,2 splice positions, so it does not qualify for default PVS1 application.
PS1
No evidence was identified showing that this variant has the same established splicing consequence as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not assessed.
PS3
Published functional and RNA studies for this exact variant showed partial impact rather than a clearly damaging effect.
PS4
No case-control dataset or other prevalence analysis was identified showing that this variant is significantly enriched in affected individuals compared with controls, so PS4 was not assessed.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified for this variant occurring with a second BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not assessed.
PP1
No informative segregation dataset was identified for this variant, so PP1 was not assessed.
PP4
No usable BRCA1 clinical-history likelihood ratio was identified for this variant, so PP4 was not assessed.
Benign
BA1
Population frequency does not meet the BRCA1 stand-alone benign threshold.
BS1
Population frequency does not meet the BRCA1 benign strong or supporting thresholds.
BS2
No qualifying observations in individuals without features of BRCA1/2-related Fanconi anemia were identified for this variant, so BS2 was not assessed.
BS3
Available functional and RNA evidence for this exact variant does not show a clearly normal effect.
BS4
No informative non-segregation dataset was identified for this variant, so BS4 was not assessed.
BP4
Computational evidence does not support a benign interpretation.
BP5
No usable benign-direction BRCA1 clinical-history likelihood ratio was identified for this variant, so BP5 was not assessed.
BP7
Benign splice evidence is not supported.
N/A · 10
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97697e-06; MAF= 0.00040%, 1/251448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79152e-06; MAF= 0.00088%, 1/113746 alleles, homozygotes = 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
0.0004%
· 1 / 251,448
0 hom
0 hom
European (non-Finnish) 1 / 113,746 |
0.00088% |
+ 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 Uncertain significance (4 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Likely 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 = 1.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links