Variant classification summary

NM_007294.4:c.3700_3704del

BRCA1 · NP_009225.1:p.(Val1234GlnfsTer8) · NM_007294.4

GRCh37: chr17:41243843 GTTTAC>G · GRCh38: chr17:43091826 GTTTAC>G

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PVS1 very strong PM5 strong PP4 strong PM2 supporting PP5 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Val1234GlnfsTer8)

gnomAD AF

3.0975594948252172e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.3700_3704del (p.Val1234GlnfsTer8) is a frameshift deletion in BRCA1 exon 10 that creates a premature termination codon, meeting PVS1 at very strong strength per ENIGMA Table 4 for PTC variants in E10(11).

2

The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (5/1,614,374 alleles; MAF 0.00031%; grpmax FAF=1.24e-06), meeting PM2_Supporting.

3

ENIGMA Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA1 exon 10(11), an exon with multiple established pathogenic PTC variants.

4

Clinical-history likelihood ratio analysis from Li et al. 2020 (PMID:31853058) yields LR = 57.23 (N_Probands = 10), meeting PP4_Strong (LR ≥18.7), indicating significant enrichment of breast/ovarian cancer phenotype in carriers.

5

The variant has been classified as Pathogenic by the ENIGMA expert panel in ClinVar (ClinVar ID 37542) and has been observed as a recurrent founder mutation in multiple Central European populations.

6

Overall classification: Pathogenic under ENIGMA Table 3 rules (1 Very Strong + ≥1 Strong). Criteria met: PVS1 (Very Strong), PM5_Strong (PTC), PP4_Strong, PM2_Supporting.

Final determination: ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3, Pathogenic rule: 1 Very Strong criterion (PVS1) plus 1 or more Strong criteria (PM5_Strong, PP4_Strong) classifies as 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	Met	NM_007294.4:c.3700_3704del is a frameshift deletion in BRCA1 exon 10 (legacy exon 11), resulting in a premature termination codon (p.Val1234GlnfsTer8) predicted to undergo nonsense-mediated decay. Loss of function is an established disease mechanism for BRCA1. The ENIGMA BRCA1 specification (v1.2) assigns PVS1 at full strength for PTC variants in exon 10(11) per Table 4.	cspec vcep_specifications_table4_v1_2_2024_11_18 pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to predicted missense substitutions where a previously classified pathogenic variant acts via the same amino acid change, or to exonic/intronic variants with the same predicted splicing impact. This variant is a frameshift deletion, not a missense substitution or splicing variant.
PS2	N/A	PS2 (de novo) is listed as Not Applicable in the ENIGMA BRCA1 CSPEC.
PS3	N/A	This is a null (frameshift) variant. The damaging effect on protein function is captured by PVS1. ENIGMA PS3 applies to missense variants with calibrated functional assay evidence per Table 9, which does not list this frameshift variant. No variant-specific functional assay is available or needed.
PS4	Not met	PS4 requires a case-control study with p-value ≤0.05 and OR ≥4 (lower CI excludes 2.0). The variant has been observed in multiple affected families across population studies (29 families in Czech population, 7 families in German population), but no formal case-control analysis meeting ENIGMA statistical thresholds was identified for this specific variant.	PMID:18489799 PMID:11802209
PS5	N/A	PS5 is not defined in the ENIGMA BRCA1 CSPEC and is not assessed.
PM1	N/A	PM1 is listed as Not Applicable in the ENIGMA BRCA1 CSPEC.
PM2	Met	The variant is absent from gnomAD v2.1 (non-cancer, exome) and present in gnomAD v4.1 at extremely low frequency (5/1,614,374 alleles; MAF 0.00031%; grpmax FAF 1.24e-06). This meets ENIGMA PM2_Supporting: absent from controls in an outbred population per gnomAD v2.1/v3.1 criteria.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	PM3 is skipped per directive.
PM4	N/A	PM4 is listed as Not Applicable in the ENIGMA BRCA1 CSPEC.
PM5	Met	This is a protein termination codon (PTC) variant in BRCA1 exon 10 (legacy exon 11), where multiple proven pathogenic PTC variants have been observed (e.g., c.5266dupC). ENIGMA Table 4 assigns PM5_Strong (PTC) for PTC variants in exon E10(11). This criterion captures the additional weight beyond PVS1 for a PTC in an exon with established pathogenic PTCs.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PM6	N/A	PM6 is listed as Not Applicable in the ENIGMA BRCA1 CSPEC.
PP1	Not met	PP1 requires quantitative co-segregation analysis with LR ≥2.08. No co-segregation LR data was identified for this variant. While the variant has been observed in multiple families, no formal co-segregation likelihood ratio meeting ENIGMA thresholds is available in the evidence.
PP2	N/A	PP2 is listed as Not Applicable in the ENIGMA BRCA1 CSPEC.
PP3	Not met	PP3 in ENIGMA applies to missense/in-frame variants in functional domains with BayesDel ≥0.28, or variants with predicted splicing impact (SpliceAI ≥0.2). This is a frameshift deletion. SpliceAI max delta score = 0.05, well below the 0.2 threshold. No computational evidence for additional splicing impact is present. The pathogenic effect is already captured by PVS1.	spliceai
PP4	Met	The variant's clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR = 57.23 (LOG(LR) = 4.047, N_Probands = 10). This exceeds the PP4_Strong threshold of LR ≥18.7 and is based on personal and family cancer history data from multigene panel testing, indicating significant enrichment of a breast/ovarian cancer phenotype in carriers compared to non-carriers.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr cspec
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	clinvar
BA1	Not met	BA1 requires filter allele frequency (FAF) > 0.1% (0.001) in gnomAD. The grpmax FAF for this variant is 1.24e-06, far below the BA1 threshold. This variant is not present at a frequency consistent with a benign polymorphism.	gnomad_v4 cspec
BS1	Not met	BS1_Supporting requires FAF > 0.00002 (0.002%) in gnomAD. The grpmax FAF is 1.24e-06 (0.000124%), which is below even the BS1_Supporting threshold. The variant is too rare in population databases to apply BS1 at any strength.	gnomad_v4 cspec
BS2	Not met	BS2 requires documented absence of Fanconi Anemia features in homozygous or compound heterozygous individuals. No proband-level data reporting absence or presence of FA phenotype was available for this variant. Without specific clinical data, BS2 cannot be applied.
BS3	N/A	This is a null (frameshift) variant. ENIGMA BS3 applies to missense variants with calibrated functional assay evidence per Table 9, which does not include this frameshift variant. The loss-of-function effect is already captured by PVS1.
BS4	Not met	BS4 requires quantitative lack-of-segregation analysis with LR ≤0.48. No segregation data showing absence of co-segregation was identified for this variant. On the contrary, the variant has been observed in multiple affected families, consistent with pathogenic segregation.
BP1	N/A	BP1 applies to silent substitutions, missense, or in-frame insertion/deletion variants outside clinically important functional domains with no splicing predicted (SpliceAI ≤0.1). This is a frameshift deletion, not covered by BP1.
BP2	N/A	BP2 is listed as Not Applicable in the ENIGMA BRCA1 CSPEC.
BP3	N/A	BP3 is listed as Not Applicable in the ENIGMA BRCA1 CSPEC.
BP4	N/A	BP4 applies to missense or in-frame insertion/deletion variants inside clinically important functional domains with no predicted impact (BayesDel ≤0.15 and SpliceAI ≤0.1). This is a frameshift deletion, not covered by BP4.
BP5	Not met	BP5 requires a combined likelihood ratio against pathogenicity (LR ≤0.48). The clinical-history LR for this variant is 57.23, which is strongly toward pathogenicity. BP5 is not applicable.	PMID:31853058
BP6	N/A	BP6 is listed as Not Applicable in the ENIGMA BRCA1 CSPEC.
BP7	N/A	BP7 applies to intronic and silent variants, or missense/in-frame variants outside functional domains, with mRNA assay showing no splicing impact. This is a frameshift deletion, not covered by BP7.

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