Variant classification summary

NM_007294.3:c.68_69del

BRCA1 · NP_009225.1:p.(Glu23ValfsTer17) · NM_007294.3

GRCh37: chr17:41276044 ACT>A · GRCh38: chr17:43124027 ACT>A

Gene: BRCA1 Transcript: NM_007294.3

Final call

Pathogenic

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Glu23ValfsTer17)

gnomAD AF

0.00011848017845223947 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 NM_007294.3:c.68_69del (NP_009225.1:p.(Glu23ValfsTer17); p.(E23Vfs*17)) variant has been reported in ClinVar as Pathogenic with expert-panel review and is also curated in OncoKB as a loss-of-function BRCA1 variant.

2

In gnomAD, the variant is present overall at AF 0.000205352 in v2.1 and 0.00011848 in v4.1, with non-founder grpmax FAF values of 5.395e-05 and 2.478e-05 respectively; this is above the ENIGMA BS1 Supporting threshold of 0.00002 but below the BA1 threshold of 0.001.

3

This 2-bp deletion causes an early frameshift with a predicted premature stop, and the ENIGMA BRCA1 specification assigns PVS1 for exon 2 truncating variants and PM5_Strong for protein-truncating variants in exon 2.

4

BRCA1 clinical-history likelihood analysis lists the equivalent c.68_69delAG variant in 202 probands with LR 1.145935772193482e+20, far above the ENIGMA PP4 Very Strong threshold of 350.

5

SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which does not create a separate PP3 or BP4 code for this protein-truncating frameshift under the ENIGMA BRCA1 rules.

Final determination: Using the ENIGMA conflicting-evidence point system, PVS1 Very Strong, PM5 Strong, PP4 Very Strong, and PP5 Supporting, offset by BS1 Supporting, yields 20 points, which is in the Pathogenic range (>=10).

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 2-bp deletion in BRCA1 exon 2 that causes an early frameshift, NP_009225.1:p.(Glu23ValfsTer17) (p.(E23Vfs*17)), with a premature termination codon. Loss of function is an established disease mechanism for BRCA1, and the ENIGMA BRCA1 specification assigns PVS1 to exon 2 protein-truncating variants.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS1	N/A	This criterion applies to predicted missense substitutions or variants with the same predicted splicing effect as a previously classified pathogenic variant. This variant is a frameshift deletion, so PS1 is not applicable.	cspec
PS2	N/A	PS2 is not used in this ENIGMA BRCA1 specification.	cspec
PS3	N/A	The curated ENIGMA functional assay tables are designed for missense and synonymous variants. No variant-specific calibrated protein functional study assignment was identified for this frameshift deletion, so PS3 is not applicable here.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	This variant has been reported as pathogenic in ClinVar, but no directly extracted case-control odds ratio or p-value meeting the ENIGMA PS4 thresholds was identified in the reviewed sources. Available evidence supports clinical importance, but PS4 was not formally established from the materials reviewed here.	clinvar cspec
PM1	N/A	PM1 is not used in this ENIGMA BRCA1 specification for this variant context.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.000205352 (58/282442) and in gnomAD v4.1 at AF 0.00011848 (191/1612084), so the ENIGMA PM2 requirement for absence from controls is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	ENIGMA applies PM3 in the setting of BRCA1- or BRCA2-related Fanconi anemia with qualifying biallelic observations. No such proband-level recessive disease evidence was identified for this variant.	cspec
PM4	N/A	PM4 is not used in this ENIGMA BRCA1 specification.	cspec
PM5	Met	In the ENIGMA BRCA1 framework, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense comparison. This frameshift creates a premature termination codon in BRCA1 exon 2, and ENIGMA Table 4 and Supplementary Table 1 assign PM5_Strong for exon 2 protein-truncating variants.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6	N/A	PM6 is not used in this ENIGMA BRCA1 specification.	cspec
PP1	Not assessed	No quantitative segregation analysis or likelihood ratio meeting the ENIGMA PP1 thresholds was identified for this variant in the reviewed sources.	cspec
PP2	N/A	PP2 is not used in this ENIGMA BRCA1 specification.	cspec
PP3	N/A	ENIGMA PP3 computational evidence is applied to missense, in-frame, silent, or relevant intronic variants. This variant is a protein-truncating frameshift deletion, so PP3 is not applicable as a separate criterion.	cspec spliceai
PP4	Met	In the BRCA1 clinical-history likelihood-ratio dataset, this variant is listed as c.68_69delAG in 202 probands with LR 1.145935772193482e+20. This value is far above the ENIGMA PP4 Very Strong threshold of 350, supporting a strong pathogenic clinical-history signal.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The non-founder filter allele frequency does not exceed the ENIGMA BA1 threshold of 0.001. The observed grpmax FAF is 5.395e-05 in gnomAD v2.1 and 2.478e-05 in gnomAD v4.1, both below the BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Met	The non-founder filter allele frequency is above the ENIGMA BS1 Supporting threshold of 0.00002 and does not exceed the BS1 Strong threshold of 0.0001. The observed grpmax FAF is 5.395e-05 in gnomAD v2.1 and 2.478e-05 in gnomAD v4.1, so BS1 is met at Supporting strength.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	ENIGMA applies BS2 using point-based observations in individuals without Fanconi anemia features. No qualifying proband-level data were identified for this variant in the reviewed sources.	cspec
BS3	N/A	The curated ENIGMA functional assay framework for BS3 is directed to missense and synonymous variants. No calibrated benign functional assay assignment was identified for this frameshift deletion, so BS3 is not applicable here.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative non-segregation analysis meeting the ENIGMA BS4 thresholds was identified for this variant in the reviewed sources.	cspec
BP1	N/A	BP1 in the ENIGMA BRCA1 framework applies to silent, missense, or in-frame variants outside clinically important domains with no predicted splice impact. This variant is a frameshift deletion, so BP1 is not applicable.	cspec
BP2	N/A	BP2 is not used in this ENIGMA BRCA1 specification.	cspec
BP3	N/A	BP3 is not used in this ENIGMA BRCA1 specification.	cspec
BP4	N/A	ENIGMA BP4 computational evidence is applied to selected missense, in-frame, silent, and intronic variants without predicted impact. This variant is a protein-truncating frameshift deletion, so BP4 is not applicable as a separate criterion.	cspec spliceai
BP5	Not met	The available clinical-history likelihood evidence is strongly in the pathogenic direction rather than the benign direction. The observed LR for c.68_69delAG is 1.145935772193482e+20, which is far above the ENIGMA benign BP5 thresholds of 0.48, 0.23, 0.05, and 0.00285, so BP5 is not met.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	BP6 is not used in this ENIGMA BRCA1 specification.	cspec
BP7	N/A	BP7 in the ENIGMA BRCA1 framework applies to silent or intronic variants, or selected non-truncating variants with RNA evidence. This variant is a frameshift deletion, so BP7 is not applicable.	cspec spliceai

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