Variant classification summary

NM_007294.4:c.68_69del

BRCA1 · NP_009225.1:p.(Glu23ValfsTer17) · NM_007294.4

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

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PVS1_Very Strong PS3_Strong PM5_Strong PP4_Very Strong PP5_Supporting BS1_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Glu23ValfsTer17)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.68_69del (p.Glu23ValfsTer17; p.E23Vfs*17) variant is reported in ClinVar as Pathogenic, including expert-panel classification by ClinGen ENIGMA, and is also described by OncoKB as an oncogenic loss-of-function alteration.

2

This variant is present in population databases, with gnomAD v2.1 AF 0.000205352 (58/282442 alleles) and gnomAD v4.1 AF 0.00011848 (191/1612084 alleles); the observed filter allele frequencies of 5.395e-05 in v2.1 and 2.478e-05 in v4.1 are below the BA1 threshold of 0.001 but within the ENIGMA BS1_Supporting range above 0.00002 and less than or equal to 0.0001.

3

ENIGMA functional data assign PS3 Strong to this variant, with calibrated assay evidence showing a damaging effect consistent with a deleterious control profile.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, which is consistent with the primary effect being protein truncation rather than splice disruption.

5

This early exon 2 frameshift introduces a premature termination codon at p.Glu23ValfsTer17, and ENIGMA exon-level rules support PVS1 at Very Strong strength and PM5 for protein-truncating variants in this exon.

Final determination: Under the ENIGMA Table 3 conflicting-evidence point system, PVS1_Very Strong, PS3_Strong, PM5_Strong, PP4_Very Strong, and PP5_Supporting outweigh BS1_Supporting, yielding a net score of 24 points and 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	This variant is a frameshift deletion in BRCA1 exon 2, predicted to cause p.(Glu23ValfsTer17). BRCA1 loss of function is an established disease mechanism, and ENIGMA Table 4 designates exon 2 protein-truncating variants for full-strength PVS1, so this evidence supports PVS1 at Very Strong strength.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	PS1 is defined for missense variants with the same amino acid change as a previously classified pathogenic variant, or for variants with the same demonstrated splicing effect as a known pathogenic variant. This frameshift deletion does not meet those use conditions.	cspec
PS2	N/A	The ENIGMA BRCA1 specification marks PS2 as not applicable for this framework, so de novo evidence was not used for this case.	cspec
PS3	Met	This variant is listed in ENIGMA Table 9 as PS3 Strong based on a calibrated functional study that showed protein function similar to pathogenic control variants. This is consistent with OncoKB describing the variant as an oncogenic loss-of-function alteration.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 oncokb
PS4	Not assessed	This variant has been reported in disease databases, but no qualifying case-control analysis with p-value less than or equal to 0.05 and odds ratio greater than or equal to 4 was identified here. Available observation data therefore do not establish PS4.	clinvar cspec
PM1	N/A	The ENIGMA BRCA1 specification marks PM1 as not applicable, so location in a mutational hotspot or critical domain was not used as an independent criterion for this variant.	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 alleles) and in gnomAD v4.1 at AF 0.00011848 (191/1612084 alleles), so the ENIGMA requirement for absence from controls for PM2_Supporting is not met.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified that this variant was observed with a second BRCA1 variant in a patient with BRCA1-related Fanconi anemia. PM3 was therefore not assessed.	cspec
PM4	N/A	The ENIGMA BRCA1 specification marks PM4 as not applicable, and this frameshift effect is already captured by the null-variant framework under PVS1.	cspec
PM5	Met	This frameshift creates a premature termination codon in BRCA1 exon 2. ENIGMA Table 4 designates exon 2 protein-truncating variants for PM5_Strong (PTC), so this variant meets PM5 at Strong strength.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	The ENIGMA BRCA1 specification marks PM6 as not applicable, so assumed de novo evidence was not used for this case.	cspec
PP1	Not assessed	No quantitative co-segregation analysis for this variant was identified, so PP1 was not assessed.	cspec vcep_pmid_17924331_easton_2007_ajhg
PP2	N/A	The ENIGMA BRCA1 specification marks PP2 as not applicable, so this criterion was not used.	cspec
PP3	N/A	PP3 in the ENIGMA BRCA1 specification is used for qualifying missense, in-frame, or non-canonical splice-impact variants. This early frameshift deletion is evaluated under the truncating-variant framework instead, so PP3 was not applied.	cspec spliceai
PP4	Met	This variant has a BRCA1 clinical-history likelihood ratio of 1.145935772193482e+20 from 202 probands in the BRCA1 clinical-history dataset. This value is far above the ENIGMA PP4_Very Strong threshold of 350, so the clinical-history evidence strongly supports pathogenicity.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	Available population data do not meet the BA1 threshold. The observed gnomAD filter allele frequencies are 5.395e-05 in v2.1 and 2.478e-05 in v4.1, both below the ENIGMA BA1 threshold of 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Met	This variant is present above the ENIGMA BS1_Supporting population threshold but below the BS1 threshold. The gnomAD v2.1 filter allele frequency is 5.395e-05 and the gnomAD v4.1 filter allele frequency is 2.478e-05, which are above 0.00002 and below or equal to 0.0001, consistent with BS1 at Supporting strength.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No qualifying observations of this variant in individuals without features of BRCA1-related Fanconi anemia were identified for the ENIGMA BS2 point system, so BS2 was not assessed.	cspec
BS3	Not met	Available functional evidence does not support a benign effect. Instead, ENIGMA Table 9 assigns this variant PS3 Strong for a damaging functional result, 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 for this variant was identified, so BS4 was not assessed.	cspec vcep_pmid_17924331_easton_2007_ajhg
BP1	N/A	BP1 in the ENIGMA BRCA1 specification applies to silent, missense, or in-frame variants outside clinically important domains without predicted splice impact. This frameshift deletion does not fit that variant class.	cspec
BP2	N/A	The ENIGMA BRCA1 specification marks BP2 as not applicable, so this criterion was not used.	cspec
BP3	N/A	The ENIGMA BRCA1 specification marks BP3 as not applicable, so repetitive-region in-frame evidence was not used.	cspec
BP4	N/A	BP4 in the ENIGMA BRCA1 specification applies to qualifying missense, in-frame, silent, or intronic variants with no predicted impact. This early frameshift deletion is not within those use conditions.	cspec spliceai
BP5	Not met	The BRCA1 clinical-history likelihood ratio for this variant is 1.145935772193482e+20 from 202 probands, which is far above the benign BP5 thresholds and strongly favors pathogenicity. BP5 is therefore not met.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	The ENIGMA BRCA1 specification marks BP6 as not applicable, so prior benign assertions alone were not used as independent evidence.	cspec
BP7	N/A	BP7 in the ENIGMA BRCA1 specification is used for selected silent, intronic, or RNA-assay contexts. This coding frameshift deletion does not fit those use conditions.	cspec

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