Variant classification summary

NM_000059.4:c.5344C>T

BRCA2 · NP_000050.3:p.(Gln1782Ter) · NM_000059.4

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

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1 very strong PM5_Strong strong PM2 supporting PP5 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gln1782Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.5344C>T (p.Gln1782Ter) is a nonsense variant in BRCA2 exon 11, creating a premature termination codon at position 1782 of 3418 amino acids. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11.

2

ENIGMA Table 4 assigns PM5_Strong (PTC) to PTC variants in BRCA2 exon 11, where other proven pathogenic PTC variants have been established.

3

The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.

4

This variant has been classified as Pathogenic by the ENIGMA expert panel in ClinVar (Variation ID 51842), supported by 9 clinical laboratory submissions.

5

Applying the ENIGMA Table 3 point system: PVS1 (Very Strong = 8 points) + PM5_Strong (PTC) (Strong = 4 points) + PM2_Supporting (Supporting = 1 point) = 13 points, which reaches the Pathogenic threshold (>= 10 points).

Final determination: ENIGMA BRCA1/BRCA2 v1.2.0 Table 3: 1 Very Strong (PVS1) + 1 Strong (PM5_Strong) satisfies the all_of Pathogenic combination rule; the point total of 14 (PVS1=8 + PM5_Strong=4 + PM2=1 + PP5=1) exceeds the Pathogenic threshold of >= 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	NM_000059.4:c.5344C>T is a nonsense variant (p.Gln1782Ter / p.Q1782*) in BRCA2 exon 11, creating a premature termination codon. Loss of function is the established disease mechanism for BRCA2. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11. The variant is on MANE Select transcript NM_000059.4.	vcep_specifications_table4_v1_2_2024_11_18 clinvar cspec
PS1	N/A	PS1 in the ENIGMA framework applies to missense substitutions at the same amino acid position as a known pathogenic variant, or to splicing variants with the same predicted splicing impact. NM_000059.4:c.5344C>T is a nonsense variant creating a stop codon, not a missense or splicing variant.	cspec
PS2	N/A	PS2 (de novo) is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set.	cspec
PS3	Not assessed	ENIGMA Table 9 (curated functional assay results) covers missense and synonymous variants only. NM_000059.4:c.5344C>T is a nonsense variant and is not listed in Table 9. No calibrated functional assay result is available for this variant under the ENIGMA PS3 framework. The functional consequence of protein truncation is addressed by PVS1.	vcep_specifications_table9_v1_2_2024_11_18
PS4	Not met	ENIGMA PS4 requires a case-control study with p-value <= 0.05 and odds ratio >= 4 (lower confidence interval excludes 2.0). No published case-control study meeting these thresholds was identified for NM_000059.4:c.5344C>T. The variant is absent from gnomAD population databases, precluding case-control comparison.	gnomad_v2 gnomad_v4 cspec
PS5	N/A	PS5 is not included in the ENIGMA BRCA1/BRCA2 CSPEC criteria set and is designated as not applicable under this framework.	cspec
PM1	N/A	PM1 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set.	cspec
PM2	Met	NM_000059.4:c.5344C>T is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Per ENIGMA PM2 rule, absence from both outbred population databases in a region with adequate read depth qualifies for PM2_Supporting.	gnomad_v2 gnomad_v4 cspec
PM5	Met	NM_000059.4:c.5344C>T is a protein termination codon (PTC) variant in BRCA2 exon 11. ENIGMA Table 4 assigns PM5_Strong (PTC) to PTC variants in exon 11, where other proven pathogenic PTC variants have been observed. The PM5_PTC code applies additive weight to PVS1-eligible truncating variants in this exon.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PM6	N/A	PM6 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set.	cspec
PP1	Not assessed	ENIGMA PP1 requires quantitative cosegregation analysis with a Bayes score meeting specific LR thresholds (Supporting >= 2.08:1, Moderate >= 4.3:1, Strong >= 18.7:1). No cosegregation LR data was identified for NM_000059.4:c.5344C>T in the available VCEP materials or published literature.	cspec
PP2	N/A	PP2 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set. PP2 (missense in a gene with low rate of benign missense variation) is not used for BRCA2.	cspec
PP3	N/A	ENIGMA PP3 applies to missense or in-frame variants inside a clinically important functional domain with BayesDel no-AF score >= 0.30, or to variants with SpliceAI >= 0.2. NM_000059.4:c.5344C>T is a nonsense variant and does not fall under PP3 rules. SpliceAI max delta = 0.00 (no splicing impact predicted). ENIGMA v1.2 specification clarification notes that PP3 should not be stacked when PVS1 is met.	cspec spliceai bayesdel
PP4	Not assessed	ENIGMA PP4 is assessed via clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058). NM_000059.4:c.5344C>T is not listed in the BRCA2 clinical-history LR spreadsheet. The related variant c.5344C>G has LR=0.70 (neutral zone, 0.48-2.08), which does not support PP4 application. No clinical-history LR data is available for c.5344C>T.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	cspec clinvar
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only) and/or v3.1 (non-cancer). NM_000059.4:c.5344C>T is absent from both gnomAD v2.1 and v4.1/v3.1.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	ENIGMA BS1 Strong requires FAF > 0.01% (FAF > 0.0001) in gnomAD; BS1_Supporting requires FAF > 0.002% (FAF > 0.00002). NM_000059.4:c.5344C>T is absent from both gnomAD v2.1 and v4.1. Allele frequency does not support BS1 at any strength.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	ENIGMA BS2 is applied in the absence of Fanconi Anemia features and requires point-based scoring per proband per Specifications Table 8. No proband-level data was available for adjudication of this criterion.	cspec
BS3	N/A	ENIGMA Table 9 (BS3 functional assay results) covers missense and synonymous variants only. NM_000059.4:c.5344C>T is a nonsense/truncating variant; BS3 is not applicable for variants that create a premature termination codon. The loss-of-function consequence is captured by PVS1.	vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4	Not assessed	ENIGMA BS4 requires quantitative lack-of-segregation analysis with LR thresholds (Supporting <= 0.48:1, Moderate <= 0.23:1, Strong <= 0.05:1). No segregation data was identified for NM_000059.4:c.5344C>T.	cspec
BP1	N/A	ENIGMA BP1 applies to silent substitutions, missense, or in-frame variants outside a clinically important functional domain with no splicing predicted (SpliceAI <= 0.1). NM_000059.4:c.5344C>T is a nonsense/truncating variant.	cspec
BP2	N/A	BP2 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set.	cspec
BP4	N/A	ENIGMA BP4 applies to missense or in-frame variants inside a clinically important functional domain with BayesDel no-AF score <= 0.18 and SpliceAI <= 0.1, or silent/intronic variants with no splicing predicted. NM_000059.4:c.5344C>T is a nonsense variant.	cspec
BP5	Not assessed	ENIGMA BP5 is assessed via clinical-history likelihood ratio (Li et al. 2020, PMID:31853058). NM_000059.4:c.5344C>T is not listed in the BRCA2 clinical-history LR spreadsheet. No data is available to support or refute BP5 for this variant.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is designated as Not Applicable in the ENIGMA BRCA1/BRCA2 CSPEC criteria set. Reliance on prior laboratory classification is replaced by the ENIGMA framework.	cspec
BP7	N/A	ENIGMA BP7 applies to silent/intronic variants or variants with mRNA assay evidence showing no damaging effect on transcript profile. NM_000059.4:c.5344C>T is a nonsense variant creating a stop codon, not a silent or intronic change.	cspec

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