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LYFE SCIENCES
Project: HERA
NM_007294.4:c.5194-12G>A
p.?  ·  BRCA1
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Legacy Engine
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Classification rationale
1

The BRCA1 c.5194-12G>A (p.?) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as pathogenic.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (2/1612068 alleles; AF 1.24064e-06; grpmax FAF 2.8e-07).

gnomad_v2 ↗ gnomad_v4 ↗
3

RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), which is consistent with a loss-of-function splice effect and supports PVS1 at Strong strength under the ENIGMA BRCA1/2 RNA framework.

cspec ↗ PMID:21394826 ↗ PMID:21673748 ↗
4

SpliceAI predicts a strong splice impact for this variant with a maximum delta score of 0.96.

spliceai ↗ cspec ↗
5

In the ENIGMA BRCA1 clinical-history model, this variant had a likelihood ratio of 12.3447 in 1 proband, which meets PP4 at Moderate strength.

PMID:31853058 ↗ cspec ↗
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
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.24064e-06; MAF= 0.00012%, 2/1612068 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69739e-06; MAF= 0.00017%, 2/1178278 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
03
Functional
No functional summary recorded.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.96).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
06
Cancer hotspots
No cancer hotspot summary recorded.