NM_007294.4:c.212+3A>G

BRCA1 · NP_009225.1:p.? · NM_007294.4

GRCh37: chr17:41258470 T>C · GRCh38: chr17:43106453 T>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Pathogenic

PS3_Strong PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

Final determination: Under ENIGMA Table 3, one Strong pathogenic criterion together with two Supporting pathogenic criteria meets the combination rule for Likely Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not assessed	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. Multiple RNA studies identified aberrant transcripts consistent with loss of function, but the exact ENIGMA PVS1(RNA) weight for this noncanonical splice-site variant was not directly resolved from the retrieved rule tables and should be confirmed before applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment vcep_supplementarytables_v1_2_2024_11_18
PS3	Met	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.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:12037674
PS4	Not met	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. The available observations do not satisfy the ENIGMA PS4 requirement.	cspec clinvar PMID:10595255
PS1	Not assessed	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. PS1 should not be applied without confirming the Table 5 splicing-comparison rule.	cspec vcep_humu_40_1557_s001
PM2	Not met	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. Because the variant is not absent from population databases, the available evidence does not support PM2.	cspec gnomad_v2 gnomad_v4
PM5	N/A	This variant is not a protein-terminating variant, so the BRCA1 ENIGMA PM5_PTC rule does not apply.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM1	N/A	PM1 is not used in this ENIGMA BRCA1 framework because domain-based interpretation is captured through other rules rather than as a standalone criterion.	cspec
PM3	Not assessed	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.	cspec
PM4	N/A	This variant is an intronic splice-region change, and PM4 is not applicable in the ENIGMA BRCA1 framework.	cspec
PM6	N/A	De novo occurrence criteria are not used in this ENIGMA BRCA1 framework.	cspec
PP3	Met	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.	cspec spliceai
PP4	Not met	The BRCA1 clinical-history likelihood-ratio table lists this variant with LR 1.06179 in 1 proband. This is below the ENIGMA PP4 Supporting threshold of 2.08, so the available clinical-history data do not support PP4.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP1	Not assessed	No quantitative co-segregation analysis was identified for this variant, so PP1 cannot be applied from the available evidence.	cspec PMID:17924331
PP2	N/A	PP2 is not used in this ENIGMA BRCA1 framework.	cspec
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The highest observed grpmax filter allele frequency is 2.9e-07, which is below the BA1 threshold of 0.001 (0.1%). The population frequency is therefore far too low to support BA1.	cspec gnomad_v4
BS1	Not met	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. The population frequency does not support BS1.	cspec gnomad_v4
BS2	Not assessed	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.	cspec
BS3	Not met	Available functional evidence does not show a normal or non-damaging effect. Instead, ENIGMA-calibrated functional data support a damaging effect on splicing and function, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation analysis was identified for this variant, so BS4 cannot be assessed from the available evidence.	cspec PMID:17924331
BP1	N/A	BP1 in this framework applies to silent, missense, or in-frame variants without predicted splice impact. This variant is an intronic splice-region change with predicted splice impact, so BP1 does not apply.	cspec spliceai
BP2	N/A	BP2 is not used in this ENIGMA BRCA1 framework.	cspec
BP3	N/A	BP3 is not used in this ENIGMA BRCA1 framework.	cspec
BP4	Not met	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. The computational evidence therefore does not support BP4.	cspec spliceai
BP5	Not met	The BRCA1 clinical-history likelihood-ratio table lists this variant with LR 1.06179 in 1 proband. This is above the BP5 Supporting cutoff of 0.48, so the available clinical-history data do not support BP5.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not used in this ENIGMA BRCA1 framework.	cspec
BP7	Not met	Available RNA studies do not show no damaging effect; instead they identify aberrant splicing consistent with loss of function. In addition, this variant is at +3 rather than at or beyond the BP7 intronic position range of +7/-21 for the bioinformatic-only rule. The available evidence does not support BP7.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.