Variant classification summary

NM_007294.4:c.5266dup

BRCA1 · NP_009225.1:p.(Gln1756ProfsTer74) · NM_007294.4

GRCh37: chr17:41209079 T>TG · GRCh38: chr17:43057062 T>TG

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PVS1 very strong PP4 very strong PS3 supporting PP5 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Gln1756ProfsTer74)

gnomAD AF

6.753775918389602e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): protein-truncating frameshift in ENIGMA exon E19(20), assigned PVS1 per ENIGMA BRCA1 Table 4, predicting p.(Gln1756ProfsTer74).

2

PS3 (Supporting): variant-specific assays show loss of BRCT-dependent nuclear foci and failure to restore homologous-recombination activity, supporting a damaging effect.

3

PP4 (Very Strong): ENIGMA clinical history reports 183 probands with LR 8.08e+19, exceeding the >=350 very-strong threshold.

4

PP5 (Supporting): ENIGMA expert panel classifies this exact variant as Pathogenic.

5

Overall Pathogenic: two Very Strong (PVS1, PP4) plus two Supporting (PS3, PP5) meet the Table 3 rule of one Very Strong plus at least two Supporting.

Final determination: Under ENIGMA BRCA1/2 VCEP v1.2 Table 3, one Very Strong pathogenic criterion plus at least two Supporting pathogenic criteria yields a Pathogenic classification.

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	Met (Very Strong): ENIGMA BRCA1 Table 4 assigns PVS1 to protein-truncating variants in exon E19(20), covering this frameshift predicting p.(Gln1756ProfsTer74).	cspec vcep_specifications_table4_v1_2_2024_11_18 PMID:14729053 PMID:23867111
PS1	N/A	Not applicable: PS1 covers missense or splice-impact variants; SpliceAI max delta 0.005 shows no splice impact for this frameshift.	cspec spliceai
PS2	N/A	Not applicable: ENIGMA BRCA1/2 v1.2 designates PS2 as not applicable, and no de novo evidence was available.	cspec
PS3	Met	Met (Supporting): assays show loss of BRCT-dependent foci and failed homologous-recombination repair; a mixed cisplatin series (1/3 neutral) caps strength at Supporting.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:14729053 PMID:23867111
PS4	Not assessed	Not assessed: no exact-variant case-control analysis meeting ENIGMA requirements (p<=0.05, OR>=4) was available.	cspec PMID:20104584
PM1	N/A	Not applicable: PM1 applies to missense/in-frame variants in critical domains; this is a frameshift.	cspec vcep_appendices_v1_2_2024_11_18
PM2	N/A	Not applicable: ENIGMA excludes insertions from PM2, and the variant is observed in gnomAD v2.1 and v4.1.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no Fanconi anemia phenotype, second BRCA1 variant, or phase-testing data were available to apply PM3.	cspec
PM4	N/A	Not applicable: ENIGMA BRCA1/2 v1.2 marks PM4 as not applicable; protein-length change is handled by PVS1.	cspec
PM5	Not assessed	Not assessed: no same-exon proven-pathogenic PTC comparator was available for the PM5_PTC rule.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6	N/A	Not applicable: ENIGMA BRCA1/2 v1.2 designates PM6 as not applicable; no unconfirmed de novo observation qualifies.	cspec
PP1	Not assessed	Not assessed: no variant-specific segregation likelihood ratio, Bayes score, or affected-relative transmission data were available.	cspec PMID:20104584
PP2	N/A	Not applicable: ENIGMA marks PP2 not applicable, and the criterion targets missense variants, not frameshifts.	cspec
PP3	N/A	Not applicable: PP3 covers missense/in-frame or splice-impact variants; this frameshift has SpliceAI max delta 0.005, below the 0.2 threshold.	cspec spliceai
PP4	Met	Met (Very Strong): ENIGMA clinical-history table reports 183 probands with LR 8.08e+19, far exceeding the >=350 very-strong threshold.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	Met	Met (Supporting): ENIGMA expert panel classifies this exact variant as Pathogenic.	clinvar
BA1	Not met	Not met: maximum non-founder population FAF is 0.000127 (gnomAD v2.1) / 0.000043 (v4.1), both below the >0.001 BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	N/A	Not applicable: ENIGMA excludes BS1 for well-established pathogenic founder variants; c.5266dup/5382insC is a documented founder mutation.	cspec gnomad_v2 gnomad_v4 PMID:20104584
BS2	Not assessed	Not assessed: no proband phenotype, chromosome-breakage, or genotype data were available to apply BS2.	cspec
BS3	Not met	Not met: available functional studies show loss-of-function, not a benign effect; the one neutral result was deemed technically unreliable.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:14729053 PMID:23867111
BS4	Not assessed	Not assessed: no evidence of non-segregation in affected relatives or segregation likelihood data was available.	cspec
BP1	N/A	Not applicable: BP1 targets silent, missense, or in-frame variants; this is a frameshift.	cspec spliceai
BP2	N/A	Not applicable: ENIGMA BRCA1/2 v1.2 explicitly marks BP2 as not applicable.	cspec
BP3	N/A	Not applicable: ENIGMA marks BP3 not applicable; this frameshift is not an in-frame repetitive-region indel.	cspec vcep_appendices_v1_2_2024_11_18
BP4	N/A	Not applicable: BP4 is restricted to missense/in-frame, silent, or intronic classes; SpliceAI max delta 0.005 does not extend it to frameshifts.	cspec spliceai
BP5	Not met	Not met: clinical-history LR is 8.08e+19, in the pathogenic direction, far above the <=0.48 benign threshold.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	Not met	Not met: the only exact-variant expert-panel assertion is ENIGMA Pathogenic, with no benign assertion present.	clinvar
BP7	N/A	Not applicable: BP7 applies to silent/intronic variants with normal RNA assay; this is a frameshift with no mRNA assay supplied.	cspec

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.