Variant classification summary

NM_007294.4:c.4065_4068del

BRCA1 · NP_009225.1:p.(Asn1355LysfsTer10) · NM_007294.4

GRCh37: chr17:41243479 CTTGA>C · GRCh38: chr17:43091462 CTTGA>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PVS1 very strong PM5 strong PP4 strong PP5 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Asn1355LysfsTer10)

gnomAD AF

3.2846869135594356e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 NM_007294.4:c.4065_4068del (NP_009225.1:p.(Asn1355LysfsTer10), p.(N1355Kfs*10)) variant has been reported in ClinVar as Pathogenic by the ENIGMA expert panel and by multiple clinical laboratories.

2

This variant is present at very low frequency in gnomAD v2.1 (3/250844 alleles; AF 1.19596e-05, 0.00120%; grpmax FAF 2.93e-06), which is below the BRCA1 BA1 and BS1 thresholds but means the variant is not absent from controls, so PM2 is not met.

3

The BRCA1 clinical-history likelihood-ratio dataset lists this deletion as c.4065_4068delTCAA in 37 probands with LR 6590.9969, supporting pathogenic clinical-history evidence under the ENIGMA BRCA1 framework.

4

This frameshift lies in BRCA1 exon 10(11) and predicts a premature stop codon at residue 1364; the ENIGMA BRCA1 exon-specific Table 4 supports PVS1 and PM5_Strong (PTC) for truncating variants in this exon.

Final determination: Pathogenic classification is supported because one very strong pathogenic criterion and at least one strong pathogenic criterion are met (PVS1 and PM5, with additional PP4 and PP5 support), which satisfies the ENIGMA Table 3 pathogenic combining rule.

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	This variant is a frameshift deletion, NM_007294.4:c.4065_4068del, predicted to create p.(Asn1355LysfsTer10) / p.(N1355Kfs*10). It lies in BRCA1 exon 10(11), where the ENIGMA BRCA1 Table 4 assigns PVS1 for protein-truncating variants, and BRCA1 loss of function is an established disease mechanism in the official gene-specific framework.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	PS1 is not applicable because this variant is a frameshift protein-truncating deletion rather than a missense change or a same-splice-effect comparison variant.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	PS2 is not applicable in this BRCA1 VCEP framework.	cspec
PS3	N/A	PS3 was not applied because the BRCA1 curated functional assay resources are intended for specific missense, synonymous, or splice-impact variants, and no calibrated protein functional assay result for this frameshift deletion was identified.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 cspec
PS4	Not assessed	The variant has been reported in ClinVar and older literature sources, but no validated BRCA1 case-control analysis with odds ratio and confidence interval meeting the ENIGMA PS4 threshold was identified.	clinvar vcep_specifications_v1_2_2024_11_18 PMID:10699917 PMID:11802209 PMID:14757871 PMID:17018160 PMID:21559243
PM1	N/A	PM1 is not applicable in this BRCA1 VCEP framework.	cspec
PM2	Not met	This variant is not absent from controls, so PM2 is not met. In gnomAD v2.1 it is present at 3/250844 alleles (AF 1.19596e-05; 0.00120%), with grpmax FAF 2.93e-06 and no homozygotes.	gnomad_v2 cspec vcep_specifications_v1_2_2024_11_18
PM3	Not assessed	No evidence was identified that this variant was observed with another BRCA1 pathogenic variant in a patient with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	PM4 is not applicable in this BRCA1 VCEP framework.	cspec
PM5	Met	In the BRCA1 ENIGMA framework, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. This frameshift lies in BRCA1 exon 10(11), and ENIGMA Table 4 assigns PM5_Strong (PTC) for truncating variants in this exon.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not applicable in this BRCA1 VCEP framework.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.	vcep_specifications_v1_2_2024_11_18 PMID:11802209 PMID:14757871
PP2	N/A	PP2 is not applicable in this BRCA1 VCEP framework.	cspec
PP3	N/A	PP3 was not applied because this is a frameshift deletion. The BRCA1 computational PP3 rule is designed for missense, in-frame, silent, or non-canonical intronic variants; REVEL and BayesDel were not available for this deletion, and SpliceAI showed only a max delta score of 0.14, below the BRCA1 PP3 splice threshold of 0.2.	cspec spliceai
PP4	Met	The BRCA1 clinical-history likelihood-ratio workbook contains this deletion as c.4065_4068delTCAA with 37 probands and LR 6590.9969. This exceeds the ENIGMA PP4 threshold for pathogenic clinical-history evidence and supports PP4.	vcep_pmid_31853058_brca1_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine PMID:31853058 vcep_specifications_v1_2_2024_11_18
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	cspec clinvar
BA1	Not met	BA1 is not met because the highest observed grpmax FAF is 2.93e-06 in gnomAD v2.1, which is well below the BRCA1 BA1 threshold of 0.001.	gnomad_v2 cspec
BS1	Not met	BS1 is not met because the highest observed grpmax FAF is 2.93e-06 in gnomAD v2.1, below both the BRCA1 BS1 supporting threshold of 0.00002 and strong threshold of 0.0001.	gnomad_v2 cspec
BS2	Not assessed	No evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the BRCA1 BS2 point-based framework, so BS2 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
BS3	N/A	BS3 was not applied because no calibrated benign functional assay result was identified for this frameshift deletion, and the BRCA1 curated BS3 resources are directed mainly to specific missense, synonymous, or splice-impact variants.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 cspec
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.	vcep_specifications_v1_2_2024_11_18 PMID:11802209 PMID:14757871
BP1	N/A	BP1 is not applicable because this variant is a frameshift deletion, whereas the BRCA1 BP1 rule applies to silent, missense, or in-frame variants outside key functional domains with no splice effect predicted.	cspec
BP2	N/A	BP2 is not applicable in this BRCA1 VCEP framework.	cspec
BP3	N/A	BP3 is not applicable in this BRCA1 VCEP framework.	cspec
BP4	N/A	BP4 was not applied because this is a frameshift deletion. The BRCA1 BP4 rule is intended for missense, in-frame, silent, or non-canonical intronic variants with benign computational evidence; REVEL and BayesDel were not available for this deletion, and SpliceAI max delta score was 0.14.	cspec spliceai
BP5	Not met	BP5 is not met because the available BRCA1 clinical-history likelihood ratio is strongly in the pathogenic direction rather than the benign direction. The matched workbook entry for c.4065_4068delTCAA shows LR 6590.9969 in 37 probands, which is far above the benign BP5 thresholds.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
BP6	N/A	BP6 is not applicable in this BRCA1 VCEP framework.	cspec
BP7	N/A	BP7 is not applicable because this variant is a frameshift coding deletion rather than a silent or eligible intronic variant.	cspec spliceai

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