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LYFE SCIENCES
Project: HERA
NM_000059.4:c.7977-1G>C
p.?  ·  BRCA2
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Initialising…
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Legacy Engine
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Classification rationale
1

The BRCA2 c.7977-1G>C (p.?) variant has been reported in ClinVar as pathogenic, including review by the ClinGen ENIGMA BRCA1/2 expert panel.

clinvar ↗
2

This variant is present at very low frequency in population databases, with 2/281032 alleles in gnomAD v2.1 (AF 7.12e-06) and 5/1612350 alleles in gnomAD v4.1 (AF 3.10e-06; grpmax FAF 1.24e-06), which is too low for BS1 or BA1 but means PM2 is not met because the variant is not absent from controls.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

A BRCA2 clinical-history likelihood-ratio analysis reported LR 7.22 across 7 probands, which meets ENIGMA PP4_Moderate.

PMID:31853058 ↗
4

RNA evidence cited by ENIGMA indicates that variants at this splice acceptor site cause leaky abnormal splicing, and ENIGMA specifically assigns c.7977-1G>C as PVS1_Strong (RNA).

PMID:16211554 ↗
5

SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 0.95, which supports splice disruption but is not separately counted as PP3 because the variant is at a canonical splice position already captured by PVS1.

spliceai ↗ 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 v2.1This variant is present in gnomAD v2.1 (AF= 7.11663e-06; MAF= 0.00071%, 2/281032 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56023e-05; MAF= 0.00156%, 2/128186 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.10106e-06; MAF= 0.00031%, 5/1612350 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.2405e-06; MAF= 0.00042%, 5/1179106 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) 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 = 0.95).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV104701362, n = 1 times).
COSMIC ↗
06
Cancer hotspots
No cancer hotspot summary recorded.