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LYFE SCIENCES
Project: HERA
NM_000059.3:c.7977-1G>C
p.?  ·  BRCA2
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Classification rationale
1

The BRCA2 c.7977-1G>C (p.?) variant has been reported in ClinVar as Pathogenic, including a Pathogenic expert-panel classification from ENIGMA.

clinvar ↗
2

This variant is present at a very low frequency in population databases, with gnomAD v2.1 AF 7.11663e-06 (2/281032 alleles) and gnomAD v4.1 AF 3.10106e-06 (5/1612350 alleles), which is below benign frequency thresholds.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

RNA studies summarized in the ENIGMA BRCA2 materials reported abnormal splicing for this variant, including exon 18 deletion and exon 17/18 deletion, and ENIGMA Table 4 assigns PVS1_Strong (RNA) at this splice acceptor because variants at this site show leaky splicing.

PMID:16211554 ↗
4

Computational splicing analysis is also strongly abnormal, with a SpliceAI maximum delta score of 0.95, consistent with splice disruption, although this prediction is not counted separately because splice-impact evidence is already captured under PVS1 in the ENIGMA framework.

spliceai ↗ cspec ↗
5

In the BRCA2 clinical-history likelihood-ratio dataset, this variant had an LR of 7.223 across 7 probands, which meets the ENIGMA threshold for PP4 at moderate strength.

PMID:31853058 ↗
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). BayesDel score = 0.308409.
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.