Variant classification summary

NM_000059.4:c.1924_1925insGG

BRCA2 · NP_000050.3:p.(Ser642TrpfsTer3) · NM_000059.4

GRCh37: chr13:32910416 T>TGG · GRCh38: chr13:32336279 T>TGG

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1_VeryStrong PM5_Strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ser642TrpfsTer3)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.1924_1925insGG (p.(Ser642TrpfsTer3), p.(S642Wfs*3)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

3

This early frameshift predicts premature truncation of BRCA2, and the ENIGMA BRCA2 specification supports full PVS1 weight with additional PM5_Strong (PTC) applicability for truncating variants in exon 11.

4

SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the ENIGMA PP3 splice threshold of 0.2 and supports a truncating rather than splice-altering mechanism.

Final determination: Pathogenic based on 1 Very Strong pathogenic criterion and 1 Strong pathogenic criterion (PVS1_VeryStrong plus PM5_Strong) under the ENIGMA BRCA1/BRCA2 Table 3 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 change, NM_000059.4:c.1924_1925insGG, predicted to cause p.(Ser642TrpfsTer3) [p.(S642Wfs*3)] with truncation very early in BRCA2. The ENIGMA BRCA2 specification recognizes loss of function as an established disease mechanism, and the exon-level Table 4 assigns exon 11 truncating variants full PVS1 weight; available SpliceAI data do not suggest an alternative splice-driven explanation (max delta score 0.01).	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18 spliceai
PS1	Not met	Available evidence does not show that this variant has the same amino acid change or the same established splice effect as a previously classified pathogenic or likely pathogenic comparator. This is a truncating frameshift variant, so the BRCA2 PS1 rules were not satisfied.	cspec spliceai
PS2	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
PS3	Not assessed	No variant-specific calibrated functional study result for NM_000059.4:c.1924_1925insGG was identified in the ENIGMA BRCA2 functional-assay table. Curated literature resources point to BRCA2 loss-of-function biology in general, but the available evidence does not provide a criterion-ready PS3 assignment for this exact allele.	vcep_specifications_table9_v1_2_2024_11_18 oncokb PMID:10570174 PMID:11239455
PS4	Not assessed	No case-control evidence or quantified excess of this variant in affected individuals versus controls was identified. Available evidence is insufficient to show a statistically significant increase in prevalence required for PS4.	cspec clinvar vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
PM2	Not assessed	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity in population databases. However, the BRCA2 ENIGMA PM2 rule requires absence in the specified non-cancer datasets with adequate local read depth, and the available evidence reviewed here did not document the required coverage threshold.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant has been observed in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia. Available evidence does not support PM3 at this time.	cspec
PM4	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
PM5	Met	This variant is a protein-truncating variant in BRCA2 exon 11. In the ENIGMA BRCA2 specification, PM5 is repurposed for truncating variants, and Table 4 shows that exon 11 is eligible for PM5_Strong (PTC), meaning a different proven pathogenic truncating variant has been established in this exon and additional pathogenic weight is allowed for another exon 11 truncating variant.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
PP1	Not assessed	No segregation data were identified for this variant. Available evidence does not show co-segregation with disease in affected family members, so PP1 cannot be applied.	cspec
PP2	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
PP3	Not met	Available computational evidence does not support PP3 under the BRCA2 ENIGMA rules. SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the PP3 splice threshold of 0.2, and this frameshift variant is not a missense or in-frame change within a domain eligible for BayesDel-based PP3 use.	cspec spliceai
PP4	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio meeting BRCA2 ENIGMA thresholds was identified. Available evidence is insufficient to apply PP4.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the BRCA2 ENIGMA BA1 threshold of filter allele frequency greater than 0.1%. BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the BRCA2 ENIGMA BS1 thresholds of filter allele frequency above 0.002% or 0.01%. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that would satisfy the ENIGMA point-based BS2 rule. Available evidence is insufficient to apply BS2.	cspec
BS3	Not assessed	No variant-specific calibrated benign functional study result for NM_000059.4:c.1924_1925insGG was identified in the ENIGMA BRCA2 functional-assay table. Available evidence does not support BS3.	vcep_specifications_table9_v1_2_2024_11_18 oncokb
BS4	Not assessed	No lack-of-segregation data were identified for this variant. Available evidence does not provide the quantitative non-segregation likelihood ratio required for BS4.	cspec
BP1	Not met	This variant is not a silent, missense, or in-frame change outside a clinically important functional domain. It is a truncating frameshift variant, so BP1 is not met.	cspec spliceai
BP2	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
BP3	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
BP4	Not met	Available computational evidence does not support BP4 for this variant under the BRCA2 ENIGMA rules. Although SpliceAI predicts no significant splice impact with a max delta score of 0.01, BP4 is restricted to eligible missense, in-frame, silent, or intronic variants, and this allele is a truncating frameshift variant.	cspec spliceai
BP5	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio in the benign direction was identified for this allele. Available evidence is insufficient to apply BP5.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification for this review context.	cspec
BP7	Not met	This variant is not a silent or intronic change, and no RNA-only benign splicing evidence specific to this allele was identified. BP7 is not met.	cspec spliceai

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