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LYFE SCIENCES
Project: HERA
NM_000059.4:c.632-3C>G
p.?  ·  BRCA2
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Legacy Engine
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Classification rationale
1

The BRCA2 c.632-3C>G (NP_000050.3:p.?) variant has been reported in ClinVar and is classified as Likely Pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel.

clinvar ↗
2

This variant is rare in population databases, with 1/243142 alleles in gnomAD v2.1 (AF 0.00041%) and 4/1590500 alleles in gnomAD v4.1 (AF 0.00025%), which is below ENIGMA BA1 and BS1 thresholds but does not meet the absence requirement for PM2.

gnomad_v2 ↗ gnomad_v4 ↗
3

RNA splicing studies reported complete splice disruption with retention of 2 intronic bases and no wild-type transcript detected from the variant allele, which is consistent with an RNA-based loss-of-function effect and supports PVS1_Strong (RNA) under the ENIGMA BRCA2 framework.

PMID:22505045 ↗
4

In silico splicing prediction also supports a spliceogenic effect, with SpliceAI max delta score 0.95, well above the ENIGMA PP3 splice threshold of 0.2, although PP3 is not scored separately when PVS1 is met.

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
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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= 4.11282e-06; MAF= 0.00041%, 1/243142 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.67913e-05; MAF= 0.00668%, 1/14972 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.51493e-06; MAF= 0.00025%, 4/1590500 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.3661e-05; MAF= 0.00537%, 4/74542 alleles, homozygotes = 0); grpmax FAF= 1.752e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (5 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as likely pathogenic (1 clinical laboratory) and as Likely 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 not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
06
Cancer hotspots
No cancer hotspot summary recorded.