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
BRCA1
Final classification
Likely Pathogenic
BRCA1 c.5561T>C · p.Leu1854Pro
BRCA1
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
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
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
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.
PMID PMID:30209399
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:30765603
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links