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.1 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.2 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.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.4
Final classification
Pathogenic
PVS1PM5
BRCA2
c.2830A>T
p.Lys944Ter
This variant
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.
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules from final_classification_framework.
Classification rationale
PVS1PM5
Pathogenic
BRCA2 c.2830A>T
PVS1 + PM5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
review
Pathogenic
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.
Nonsense variant p.(Lys944Ter)/p.(K944*)BRCA2 loss of function is an established disease mechanismBRCA2 exon 11 is PVS1-applicable in ENIGMA Table 4
PM5
strong
review
Pathogenic
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.
Variant is a protein truncating variantBRCA2 exon 11 carries PM5_Strong (PTC) in ENIGMA Table 4
Assessed · not applied
· 3 not met · 9 not assessed
Pathogenic
PS3
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.
PS4
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.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified that this variant was observed in trans in an individual with BRCA2-related Fanconi anemia.
PP1
No quantitative co-segregation analysis meeting ENIGMA BRCA2 PP1 thresholds was identified.
PP4
No multifactorial likelihood analysis meeting ENIGMA BRCA2 PP4 thresholds was identified.
Benign
BA1
Population frequency does not meet BA1.
BS1
Population frequency does not meet BS1.
BS2
No individual-level evidence meeting the ENIGMA BRCA2 BS2 point-based framework was identified.
BS3
No well-established functional study showing no damaging effect, and no ENIGMA Table 9 benign assignment, was identified for this variant.
BS4
No quantitative lack-of-segregation analysis meeting ENIGMA BRCA2 BS4 thresholds was identified.
BP5
No multifactorial likelihood analysis meeting ENIGMA BRCA2 BP5 thresholds was identified.
N/A · 14
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.71824e-06; MAF= 0.00037%, 6/1613668 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33461e-05; MAF= 0.00133%, 1/74928 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.06375e-05; MAF= 0.00106%, 3/282020 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.02123e-05; MAF= 0.00402%, 1/24868 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,613,668
0 hom · FAF 7.9e-05%
0 hom · FAF 7.9e-05%
African/African American 1 / 74,928 |
0.0013% |
South Asian 1 / 91,010 |
0.0011% |
European (non-Finnish) 4 / 1,179,850 |
0.00034% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0011%
· 3 / 282,020
0 hom
0 hom
African/African American 1 / 24,868 |
0.004% |
South Asian 1 / 30,514 |
0.0033% |
European (non-Finnish) 1 / 128,752 |
0.00078% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Pathogenic (37 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66450359, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
BRCA1 and BRCA2 genetic testing in Italian breast and/or ovarian cancer families
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
very strong
Identification of a novel in-frame deletion in BRCA2 and analysis of variants of
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
very strong
Sources & reference links