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LYFE SCIENCES
Project: HERA
NM_007294.3:c.5561T>C
p.Leu1854Pro  ·  BRCA1
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Classification rationale
1

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.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

PMID:30209399 ↗ PMID:30765603 ↗
4

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.

cspec ↗ spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.731. BayesDel score = 0.406711.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueL1854
Hotspots ↗