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.1 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 PM2.2 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.3 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.4
BRCA2
Final classification
Uncertain significance
BRCA2 c.632-3C>G · p.?
BRCA2
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.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework override from CSPEC/final_classification_framework was applied.
Classification rationale
PVS1PP5
Uncertain significance
BRCA2 c.632-3C>G
PVS1 + PP5
→
Uncertain significance
2
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
3
PMID:22505045 ↗vcep_humu_40_1557_s001vcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
4
spliceai ↗vcep_specifications_v1_2_2024_11_18
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,590,500
0 hom · FAF 0.0018%
0 hom · FAF 0.0018%
African/African American 4 / 74,542 |
0.0054% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.00041%
· 1 / 243,142
0 hom
0 hom
African/African American 1 / 14,972 |
0.0067% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.95).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:22505045
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:31131967
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
Sources & reference links