LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-21
Case ID: NM_000059.4_c.2830A_T_20260421_151937
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.2830A>T

BRCA2  · NP_000050.3:p.(Lys944Ter)  · NM_000059.4
GRCh37: chr13:32911322 A>T  ·  GRCh38: chr13:32337185 A>T
Gene: BRCA2 Transcript: NM_000059.4
Final call
Pathogenic
PVS1_VeryStrong PM5_Strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Lys944Ter)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The BRCA2 c.2830A>T (p.Lys944Ter; p.K944*) variant has been reported in ClinVar as pathogenic by an expert panel and is classified by OncoKB as likely oncogenic with likely loss of function.
2
This variant is present at very low frequency in gnomAD, with AF 1.06375e-05 (3/282020 alleles) in v2.1 and AF 3.71824e-06 (6/1613668 alleles) in v4.1, which is below ENIGMA BRCA2 BS1 and BA1 thresholds but means PM2 is not met because the variant is not absent from controls.
3
This nonsense variant occurs in BRCA2 exon 11, a PVS1-eligible exon in the ENIGMA BRCA2 specification, and exon 11 protein termination codon variants are assigned PM5_Strong (PTC), supporting a loss-of-function interpretation.
4
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.
Final determination: Pathogenic based on 1 Very Strong pathogenic criterion (PVS1) and 1 Strong pathogenic criterion (PM5) under 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 nonsense change, NM_000059.4:c.2830A>T (p.Lys944Ter; p.K944*), in BRCA2, a gene in which loss of function is an established disease mechanism. The variant is located in exon 11, which is designated as PVS1-applicable in the ENIGMA BRCA2 specification, and the predicted premature stop is consistent with a loss-of-function effect.
cspec pvs1_gene_context pvs1_variant_assessment vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8
PS1 N/A PS1 is not applicable because this is a protein truncating variant, not a missense variant or a same-splice-consequence comparison against a previously classified pathogenic variant.
cspec
PS2 N/A PS2 is not applicable under the ENIGMA BRCA2 specification.
cspec
PS3 Not assessed Available evidence supports loss of BRCA2 function for truncating variants in general, but no variant-specific calibrated functional study or ENIGMA Table 9 assignment was identified for this variant. The available data therefore do not support formal PS3 application.
oncokb vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8 PMID:10570174 PMID:11239455
PS4 Not assessed This variant has been reported in affected individuals and is listed in ClinVar as pathogenic, but no case-control study meeting the ENIGMA BRCA2 PS4 requirement of p≤0.05 with OR≥4 and lower confidence interval excluding 2.0 was identified. The available evidence is therefore insufficient for PS4.
clinvar cspec PMID:16760289 PMID:20104584 PMID:23096105
PM1 N/A PM1 is not applicable under the ENIGMA BRCA2 specification.
cspec
PM2 Not met This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 1.06375e-05 (3/282020 alleles) and in gnomAD v4.1 at AF 3.71824e-06 (6/1613668 alleles), so the ENIGMA BRCA2 requirement for absence from controls is not met.
gnomad_v2 gnomad_v4 cspec
PM3 Not assessed No evidence was identified that this variant was observed in trans in an individual with BRCA2-related Fanconi anemia. PM3 was therefore not assessed.
cspec
PM4 N/A PM4 is not applicable under the ENIGMA BRCA2 specification.
cspec
PM5 Met This protein truncating variant occurs in BRCA2 exon 11. In the ENIGMA BRCA2 exon-level Table 4, exon 11 protein termination codon variants are assigned PM5_Strong (PTC), so PM5 is met at strong strength in addition to PVS1.
cspec vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8
PM6 N/A PM6 is not applicable under the ENIGMA BRCA2 specification.
cspec
PP1 Not assessed No quantitative co-segregation analysis meeting ENIGMA BRCA2 PP1 thresholds was identified. PP1 was therefore not assessed.
cspec
PP2 N/A PP2 is not applicable under the ENIGMA BRCA2 specification.
cspec
PP3 N/A PP3 is not applicable because this is a nonsense variant rather than a missense, in-frame, silent, or non-canonical intronic variant evaluated by the ENIGMA BRCA2 in silico rules. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
cspec spliceai
PP4 Not assessed No multifactorial likelihood analysis meeting ENIGMA BRCA2 PP4 thresholds was identified. PP4 was therefore not assessed.
cspec
PP5 N/A PP5 is not applicable under the ENIGMA BRCA2 specification.
cspec
BA1 Not met Population frequency does not meet BA1. The highest observed gnomAD v4.1 filter allele frequency is 7.9e-07, which is below the ENIGMA BRCA2 BA1 threshold of 0.001, and the observed allele counts are also very low.
gnomad_v4 gnomad_v2 cspec
BS1 Not met Population frequency does not meet BS1. The highest observed gnomAD v4.1 filter allele frequency is 7.9e-07, which is below the ENIGMA BRCA2 BS1_Supporting threshold of 0.00002 and far below the BS1 threshold of 0.0001.
gnomad_v4 gnomad_v2 cspec
BS2 Not assessed No individual-level evidence meeting the ENIGMA BRCA2 BS2 point-based framework was identified. BS2 was therefore not assessed.
cspec
BS3 Not assessed No well-established functional study showing no damaging effect, and no ENIGMA Table 9 benign assignment, was identified for this variant. BS3 was therefore not assessed.
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8
BS4 Not assessed No quantitative lack-of-segregation analysis meeting ENIGMA BRCA2 BS4 thresholds was identified. BS4 was therefore not assessed.
cspec
BP1 N/A BP1 is not applicable because this is a nonsense variant rather than a silent, missense, or in-frame variant.
cspec
BP2 N/A BP2 is not applicable under the ENIGMA BRCA2 specification.
cspec
BP3 N/A BP3 is not applicable under the ENIGMA BRCA2 specification.
cspec
BP4 N/A BP4 is not applicable because this is a nonsense variant rather than a missense, in-frame, silent, or non-canonical intronic variant assessed under the ENIGMA BRCA2 BP4 framework. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
cspec spliceai
BP5 Not assessed No multifactorial likelihood analysis meeting ENIGMA BRCA2 BP5 thresholds was identified. BP5 was therefore not assessed.
cspec
BP6 N/A BP6 is not applicable under the ENIGMA BRCA2 specification.
cspec
BP7 N/A BP7 is not applicable because this is a nonsense variant rather than a silent or intronic variant, or a missense/in-frame variant in the specific RNA-only contexts defined by ENIGMA BRCA2. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
cspec spliceai
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