Variant classification summary

NM_000059.4:c.5350_5351del

BRCA2 · NP_000050.3:p.(Asn1784HisfsTer2) · NM_000059.4

GRCh37: chr13:32913836 CAA>C · GRCh38: chr13:32339699 CAA>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1_VeryStrong PM5_Strong PP4_VeryStrong PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Asn1784HisfsTer2)

gnomAD AF

2.5425725873466705e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 NM_000059.4:c.5350_5351del (NP_000050.3:p.(Asn1784HisfsTer2); p.(N1784Hfs*2)) variant has been reported in ClinVar with an expert-panel Pathogenic classification, and curated somatic review resources describe it as a likely loss-of-function BRCA2 alteration.

2

This variant is present in population databases at low frequency, including 1/31,198 alleles in gnomAD v2.1 (AF 3.20533e-05) and 41/1,612,540 alleles in gnomAD v4.1 (AF 2.54257e-05; grpmax FAF 2.315e-05), which is too high for PM2 but far below BA1.

3

The variant is a frameshift deletion predicted to truncate BRCA2 after codon 1784, and the ENIGMA BRCA2 exon-level table designates exon 11 as eligible for full-strength PVS1 and PM5_Strong (PTC).

4

Clinical-history modeling for BRCA2 reports a likelihood ratio of 812.95 from 42 probands, exceeding the ENIGMA Very Strong PP4 threshold of 350; SpliceAI shows no separate splice signal (max delta 0.00).

Final determination: Pathogenic based on 1 Very Strong and 1 Strong pathogenic criterion under ENIGMA Table 3; additional Very Strong and Supporting pathogenic evidence are also present.

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.(Asn1784HisfsTer2), truncating BRCA2 shortly after codon 1784. In the ENIGMA BRCA2 specification, loss of function is an established disease mechanism, and exon 11 is designated as PVS1-applicable; therefore full-strength PVS1 is met.	cspec vcep_specifications_table4_v1_2_2024_11_18 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This is a frameshift truncating variant, not a missense substitution or alternate variant with the same established splicing effect as a reference pathogenic variant. PS1 is therefore not applicable.	cspec
PS2	N/A	The BRCA2 specification does not use PS2 for this framework, so this criterion is not applicable.	cspec
PS3	Not assessed	No variant-specific calibrated functional study assigning PS3 for this variant was identified. General BRCA2 loss-of-function literature supports disease mechanism but does not by itself establish PS3 for this specific variant.	vcep_specifications_table9_v1_2_2024_11_18 oncokb PMID:10570174 PMID:11239455 PMID:22193408
PS4	Not assessed	The variant has been reported clinically, but no qualifying case-control study demonstrating a significant enrichment in affected individuals with p-value ≤0.05 and odds ratio ≥4 was identified. PS4 is not assessed from the available evidence.	clinvar cspec
PM1	N/A	PM1 is not used in the BRCA2 ENIGMA framework for this variant class.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/31,198 alleles (AF 3.20533e-05) and in gnomAD v4.1 at 41/1,612,540 alleles (AF 2.54257e-05), so PM2 is not met.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified showing this variant in trans with another BRCA2 variant in an individual with phenotype consistent with BRCA2-related Fanconi anemia. PM3 is not assessed.	cspec
PM4	N/A	PM4 is not used in the BRCA2 ENIGMA framework, so this criterion is not applicable.	cspec
PM5	Met	In the BRCA2 ENIGMA framework, PM5 is repurposed for truncating variants. This frameshift creates a premature termination codon in exon 11, and ENIGMA Table 4 assigns exon 11 a PM5_Strong (PTC) designation, so PM5 is met at Strong strength.	cspec vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6	N/A	The BRCA2 specification does not use PM6 in this framework, so this criterion is not applicable.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence.	cspec
PP2	N/A	PP2 is not used in the BRCA2 ENIGMA framework, so this criterion is not applicable.	cspec
PP3	N/A	PP3 in the BRCA2 specification is used for qualifying missense, in-frame, or non-canonical splice-impact variants. This variant is a frameshift deletion, and SpliceAI shows no separate splice signal (max delta 0.00), so PP3 is not applicable.	cspec spliceai
PP4	Met	This variant has a BRCA2 clinical-history likelihood ratio of 812.95 based on 42 probands in the ENIGMA-supported Li et al. dataset. This value is above the Very Strong threshold of 350, so PP4 is met at Very Strong strength.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	cspec clinvar
BA1	Not met	Population frequency is well below the BA1 threshold. gnomAD v4.1 shows a grpmax FAF of 2.315e-05, which is far below the BRCA2 BA1 threshold of 0.001, and gnomAD v2.1 does not show evidence of a high-frequency founder or non-founder signal. BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Available population data do not support BS1. gnomAD v4.1 shows a grpmax FAF of 2.315e-05, which is below the Strong threshold of 0.0001, and no framework-qualifying benign population signal was identified for this variant. BS1 is not met.	gnomad_v4 gnomad_v2 cspec
BS2	Not assessed	No qualifying observations in individuals lacking features of BRCA2-related Fanconi anemia were identified to support BS2. This criterion is not assessed.	cspec
BS3	Not assessed	No variant-specific calibrated functional study showing no damaging effect was identified for this variant. BS3 is not assessed.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation likelihood-ratio data were identified for this variant, so BS4 cannot be assessed.	cspec
BP1	N/A	BP1 in this framework applies to qualifying silent, missense, or in-frame variants outside clinically important domains. This variant is a frameshift truncating variant, so BP1 is not applicable.	cspec
BP2	N/A	BP2 is not used in the BRCA2 ENIGMA framework, so this criterion is not applicable.	cspec
BP3	N/A	BP3 is not used in the BRCA2 ENIGMA framework, so this criterion is not applicable.	cspec
BP4	N/A	BP4 in the BRCA2 specification applies to qualifying missense, in-frame, silent, or intronic variants with no predicted impact. Although SpliceAI predicts no significant splice effect (max delta 0.00), this variant is a frameshift truncating deletion, so BP4 is not applicable.	cspec spliceai
BP5	Not met	The available multifactorial clinical-history evidence does not support BP5. The BRCA2 likelihood ratio is 812.95, which is far above the benign BP5 threshold of 0.48 and instead supports pathogenicity.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	N/A	BP6 is not used in the BRCA2 ENIGMA framework, so this criterion is not applicable.	cspec
BP7	N/A	BP7 applies to qualifying silent or intronic variants, and in some RNA-only contexts, not to a frameshift truncating deletion. BP7 is therefore not applicable.	cspec

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