The BRCA1 c.212+3A>G (p.?) variant has been reported in ClinVar as pathogenic by the ClinGen ENIGMA expert panel and by multiple clinical laboratories.1 This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low frequency of 2/1574274 alleles (AF 1.27043e-06; 0.00013%), which is below the BA1 and BS1 population thresholds.2 ENIGMA-calibrated functional evidence supports a damaging effect: Table 9 assigns PS3_Strong for BRCA1 c.212+3A>G, and supplementary ENIGMA datasets classify the variant as having complete functional impact with multiple RNA assays showing aberrant splicing consistent with loss of function.3 SpliceAI predicts a deleterious splicing effect with a maximum delta score of 0.63, which exceeds the ENIGMA PP3 threshold of 0.2 for intronic variants outside the canonical +/-1,2 splice positions.4
Final classification
Likely Pathogenic
PS3PP3PP5
BRCA1
c.212+3A>G
p.?
This variant
The BRCA1 c.212+3A>G (p.?) variant has been reported in ClinVar as pathogenic by the ClinGen ENIGMA expert panel and by multiple clinical laboratories.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official ClinGen CSPEC/VCEP criteria-combination rules).
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA1 c.212+3A>G
PS3 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:12037674 ↗
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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_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
Available ENIGMA-calibrated functional evidence supports a damaging effect for this variant. ENIGMA Table 9 assigns PS3 at Strong strength for BRCA1 c.212+3A>G, and the supplementary tables classify the variant as having complete functional impact with multiple assays showing aberrant splicing consistent with loss of function.
ENIGMA Table 9 lists BRCA1 c.212+3A>G as PS3 Strong.Supplementary Table 4 classifies c.212+3A>G as Functional impact - complete.Supplementary splicing tables summarize 5/6 assays as supporting out-of-frame aberrant transcripts consistent with loss of function.
PP3
supporting
review
Pathogenic
SpliceAI predicts a splice effect for this variant with a maximum delta score of 0.63, which is above the ENIGMA PP3 threshold of 0.2 for intronic variants outside the +/-1,2 splice positions. This computational evidence supports a deleterious effect on splicing.
SpliceAI max delta score = 0.63.ENIGMA PP3 threshold for predicted splicing impact is SpliceAI >=0.2.
PP5
supporting
review
Pathogenic
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
The BRCA1 ENIGMA specification marks PP5 as not applicable.ClinVar classifications are available but do not substitute for independent evidence review under this framework.ClinVar expert panel classification
Assessed · not applied
· 9 not met · 6 not assessed
Pathogenic
PVS1
This intronic donor-site variant is at position +3 rather than the canonical +/-1,2 splice positions, so it does not meet the default null-variant PVS1 bucket in the generic scaffold.
PS1
Pathogenic splice donor variants at the same exon/intron boundary have been described, but the exact ENIGMA positional weighting needed to determine whether this variant has the same splicing effect as a previously classified pathogenic variant was not directly resolved from the retrieved materials.
PS4
This variant has been reported in affected individuals and as a founder mutation in the literature, but no case-control study with p-value <=0.05 and odds ratio >=4 with the lower confidence interval excluding 2.0 was identified from the retrieved evidence.
PM2
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 1.27043e-06 (0.00013%; 2/1574274 alleles), with highest observed population AF 1.74444e-06 and grpmax FAF 2.9e-07.
PM3
No evidence was identified that this variant was observed with a second BRCA1 variant in an individual with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 cannot be evaluated from the available data.
PP1
No quantitative co-segregation analysis was identified for this variant, so PP1 cannot be applied from the available evidence.
PP4
The BRCA1 clinical-history likelihood-ratio table lists this variant with LR 1.06179 in 1 proband.
Benign
BA1
The highest observed grpmax filter allele frequency is 2.9e-07, which is below the BA1 threshold of 0.001 (0.1%).
BS1
The highest observed grpmax filter allele frequency is 2.9e-07, which is below the BS1 Supporting threshold of 0.00002 and below the BS1 Strong threshold of 0.0001.
BS2
No evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia in a way that satisfies the ENIGMA point-based BS2 framework.
BS3
Available functional evidence does not show a normal or non-damaging effect.
BS4
No quantitative lack-of-segregation analysis was identified for this variant, so BS4 cannot be assessed from the available evidence.
BP4
SpliceAI predicts splice impact with a maximum delta score of 0.63, which is above the BP4 threshold of 0.1 for intronic variants outside the canonical splice positions.
BP5
The BRCA1 clinical-history likelihood-ratio table lists this variant with LR 1.06179 in 1 proband.
BP7
Available RNA studies do not show no damaging effect; instead they identify aberrant splicing consistent with loss of function.
N/A · 9
PM1 · PM4 · PM5 · PM6 · PP2 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.27043e-06; MAF= 0.00013%, 2/1574274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74444e-06; MAF= 0.00017%, 2/1146498 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00013%
· 2 / 1,574,274
0 hom · FAF 2.9e-05%
0 hom · FAF 2.9e-05%
European (non-Finnish) 2 / 1,146,498 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as not provided (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as 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 = 0.63).
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
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Pathological splice mutations outside the invariant AG/GT splice sites of BRCA1
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links