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
Final classification
Uncertain significance
PVS1PP5
BRCA2
c.632-3C>G
p.?
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
strong
review
Pathogenic
This intronic variant is outside the canonical ±1,2 splice positions, but RNA studies identified complete splice disruption with retention of 2 intronic bases and no wild-type transcript detected from the variant allele. Under the ENIGMA BRCA2 splicing framework, mRNA-only evidence for a noncanonical splice variant with apparent near-complete aberrant splicing supports PVS1 at RNA-adjusted strength rather than PS3.
Splicing assay result: complete effectAllele-specific assay reportedNo wild-type transcript reported
PP5
supporting
review
Pathogenic
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
ClinVar expert panel classification
Assessed · not applied
· 11 not met · 6 not assessed
Pathogenic
PS1
No directly matched pathogenic or likely pathogenic reference variant with the same predicted splicing event was identified from the reviewed evidence, so PS1 was not assessed.
PS3
Available functional evidence is an mRNA splicing assay rather than a protein function assay.
PS4
No qualifying case-control odds ratio or proband-counting evidence meeting ENIGMA PS4 requirements was identified for this variant.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified for this variant occurring with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia, so PM3 was not assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
PP3
SpliceAI predicts a strong splice effect for this variant (max delta score 0.95, above the PP3 threshold of 0.2), but the ENIGMA BRCA2 specification states that PP3 should not be applied when PVS1 is met at any strength.
PP4
Clinical-history likelihood data do not reach the ENIGMA PP4 threshold.
Benign
BA1
Population frequency does not meet the ENIGMA BA1 threshold.
BS1
Population frequency does not meet the ENIGMA BS1 threshold.
BS2
No evidence was identified showing this variant in trans with another BRCA2 variant in individuals lacking Fanconi anemia features, so BS2 was not assessed.
BS3
No benign protein-function evidence was identified for this variant.
BS4
No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.
BP1
This criterion is not met because the variant is intronic and predicted to alter splicing.
BP4
This criterion is not met because computational evidence predicts splice disruption.
BP5
Clinical-history likelihood data do not meet ENIGMA BP5 thresholds.
BP7
This criterion is not met because the variant is at position c.632-3, which is not outside the low-conservation intronic region used for BP7 in BRCA2, and both prediction and RNA evidence show splice disruption rather than no impact.
N/A · 9
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6
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.
Guidelines for splicing analysis in molecular diagnosis derived from a set of 32
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 v
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
Sources & reference links