Variant classification summary

NM_000059.4:c.7673_7674delAG

BRCA2 · NP_000050.3:p.(Glu2558ValfsTer7) · NM_000059.4

GRCh37: chr13:32931931 CAG>C · GRCh38: chr13:32357794 CAG>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1_VeryStrong PM5_Strong PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Glu2558ValfsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.7673_7674delAG (p.Glu2558ValfsTer7; p.E2558Vfs*7) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.

2

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1,613,678 alleles; total AF 6.197e-07; highest observed population AF 1.098e-05 in South Asian individuals), supporting extremely low population frequency but not complete absence from population databases.

3

Under the ENIGMA BRCA2 loss-of-function framework, this exon 16 frameshift is eligible for PVS1, and the exon-level truncating-variant table assigns additional PM5_PTC evidence at Strong strength for this exon.

4

SpliceAI predicts possible splice impact with a maximum delta score of 0.24, while REVEL and BayesDel are not applicable to this deletion; this computational result was reviewed but not used as separate PP3 evidence because the variant was adjudicated through the loss-of-function framework.

Final determination: Pathogenic based on PVS1 at Very Strong strength together with PM5 at Strong strength under the ENIGMA BRCA1/2 criteria-combination rules.

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 predicted to produce p.(Glu2558ValfsTer7). Under the ENIGMA BRCA2 specification, loss of function is an established disease mechanism for BRCA2, and exon 16 is annotated as eligible for PVS1; therefore this truncating variant meets 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 intended for variants with the same amino acid change as a previously classified pathogenic variant, or the same predicted splicing effect as a known pathogenic splice variant. This frameshift deletion was not evaluated under a same-amino-acid-change or same-splice-outcome PS1 scenario.	cspec
PS2	N/A	No de novo framework was applicable for this review.	cspec
PS3	Not assessed	No variant-specific calibrated functional assay result for this deletion was identified in the ENIGMA BRCA2 functional assay table, so PS3 was not applied.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control dataset or other quantified enrichment evidence meeting the ENIGMA PS4 requirement was identified. Available observations are insufficient to show a statistically increased prevalence in affected individuals compared with controls.	cspec clinvar
PM1	N/A	PM1 is not used for this BRCA2 review framework.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but is present once in gnomAD v4.1 (1/1,613,678 alleles; total AF 6.197e-07; highest observed population AF 1.098e-05 in South Asian individuals). Because the ENIGMA PM2 rule requires absence from control datasets, PM2 was not applied.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed with another BRCA2 variant in a patient with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not applied.	cspec
PM4	N/A	PM4 is not used for this BRCA2 review framework.	cspec
PM5	Met	This variant creates a premature termination codon in BRCA2 exon 16. In the ENIGMA BRCA2 exon-level truncating-variant table, exon 16 is annotated for PM5_PTC at Strong strength, indicating that a different proven pathogenic truncating variant has been established in this exon and supporting additional pathogenic weight.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	No assumed de novo framework was applicable for this review.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	PP2 is not used for this BRCA2 review framework.	cspec
PP3	N/A	SpliceAI predicts possible splice impact with a maximum delta score of 0.24, but PP3 was not applied because this is a frameshift deletion already evaluated under the loss-of-function framework. REVEL and BayesDel were not available for this deletion, and the ENIGMA PP3 rule is not the primary route for this variant type.	cspec spliceai
PP4	Not met	In the BRCA2 clinical-history likelihood-ratio dataset, this variant has LR 1.833 in 1 proband. This is below the ENIGMA PP4 Supporting threshold of 2.08, so PP4 was not applied.	cspec PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant does not meet the ENIGMA BA1 threshold. It is absent from gnomAD v2.1 and is present once in gnomAD v4.1 with total AF 6.197e-07, far below the BA1 stand-alone threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant does not meet the ENIGMA BS1 threshold. It is absent from gnomAD v2.1 and present once in gnomAD v4.1 with total AF 6.197e-07 and highest observed population AF 1.098e-05, which are below the BS1 Supporting threshold of 0.00002 and the Strong threshold of 0.0001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 scoring framework, so BS2 was not applied.	cspec
BS3	Not assessed	No variant-specific calibrated functional study showing no damaging effect was identified for this deletion, so BS3 was not applied.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 was not applied.	cspec
BP1	N/A	BP1 is intended for silent, missense, or in-frame variants outside clinically important domains without predicted splice impact, and does not apply to this frameshift deletion.	cspec
BP2	N/A	BP2 is not used for this BRCA2 review framework.	cspec
BP3	N/A	BP3 is not used for this BRCA2 review framework.	cspec
BP4	N/A	BP4 is intended for missense, in-frame, silent, or certain intronic variants without predicted impact. This frameshift deletion is not an eligible BP4 variant type.	cspec spliceai
BP5	Not met	In the BRCA2 clinical-history likelihood-ratio dataset, this variant has LR 1.833 in 1 proband. This is above the BP5 Supporting threshold of 0.48, so BP5 was not applied.	cspec PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr
BP6	N/A	BP6 is not used for this BRCA2 review framework.	cspec
BP7	N/A	BP7 is intended for silent or certain intronic variants with no evidence of splice disruption, and does not apply to this frameshift deletion.	cspec spliceai

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.