The BRCA1 c.5561T>C (p.Leu1854Pro) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classifies it as likely pathogenic.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.2 In calibrated BRCA1 functional studies summarized by ENIGMA, this variant showed damaging loss-of-function behavior consistent with pathogenic control variants in two studies, supporting PS3_Strong.3 This missense change lies in the BRCA1 BRCT repeat domain; BayesDel no-AF is 0.406711, which is above the ENIGMA PP3 threshold of 0.28, REVEL is 0.731, and SpliceAI predicts no significant splice impact with a max delta score of 0.00, supporting a deleterious protein effect rather than a splicing effect.4
Final classification
Likely Pathogenic
PS3PP3PP5
BRCA1
c.5561T>C
p.Leu1854Pro
This variant
The BRCA1 c.5561T>C (p.Leu1854Pro) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classifies it as likely pathogenic.
Official ClinGen ENIGMA BRCA1/BRCA2 specification v1.2 final-classification framework using Table 3 criteria-combination rules.
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA1 c.5561T>C
PS3 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18PMID:30209399 ↗PMID:30765603 ↗
4
cspec ↗bayesdelrevelspliceai ↗vcep_appendices_v1_2_2024_11_18
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 · 3 applied · 14 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
PS3
strong
Pathogenic
In calibrated BRCA1 functional studies summarized by the ENIGMA expert panel, c.5561T>C (p.Leu1854Pro) showed damaging loss-of-function behavior similar to pathogenic control variants in two studies, supporting PS3_Strong.
ENIGMA Table 9: PS3 Strong for c.5561T>CFindlay 2018 reported LOFFernandes 2019 reported pathogenic/damaging effect
PP3
supporting
Pathogenic
This missense variant lies in the BRCA1 BRCT repeat domain, where ENIGMA allows PP3 for variants with predicted protein impact. BayesDel no-AF is 0.406711, which is above the ENIGMA PP3 threshold of 0.28, REVEL is 0.731, and SpliceAI shows no predicted splice effect (max delta score 0.00), supporting a deleterious protein effect and meeting PP3_Supporting.
BRCT domain aa 1650-1857BayesDel no-AF 0.406711 (>0.28 threshold)REVEL 0.731
Assessed · not applied
· 6 not met · 8 not assessed
Pathogenic
PS1
No previously classified pathogenic variant producing the same amino acid substitution was identified, so PS1 is not met.
PS4
No case-control study or other quantitative evidence showing that this variant is significantly enriched in affected individuals versus controls was identified, so PS4 was not assessed.
PM2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity.
PM3
No evidence was identified that this variant occurred with another BRCA1 pathogenic variant in a patient with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not assessed.
PP1
No quantitative segregation data were identified for this variant, so PP1 was not assessed.
PP4
No calibrated BRCA1 clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this exact variant, so PP4 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BS1 thresholds of filter allele frequency greater than 0.002% or greater than 0.01%.
BS2
No evidence was identified from unaffected individuals or from BRCA1-related recessive disease point scoring to support BS2, so this criterion was not assessed.
BS3
Available calibrated functional evidence does not show retained normal BRCA1 function for this variant.
BS4
No quantitative non-segregation data were identified for this variant, so BS4 was not assessed.
BP1
This missense variant is located in the BRCA1 BRCT functional domain rather than outside a clinically important domain, so the ENIGMA BP1_Strong rule is not met.
BP4
ENIGMA BP4 for missense variants in a clinically important domain requires BayesDel no-AF at or below 0.15 and SpliceAI at or below 0.1.
BP5
No calibrated BRCA1 clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this exact variant, so BP5 was not assessed.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · 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.
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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.731. BayesDel score = 0.406711.
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.
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.
Accurate classification of BRCA1 variants with saturation genome editing.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Impact of amino acid substitutions at secondary structures in the BRCT domains o
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links