The BRCA2 c.8164A>G (p.Thr2722Ala) variant has not been observed in COSMIC and has been reported in ClinVar as Likely Pathogenic, including expert-panel review by ClinGen ENIGMA BRCA1/2.1 This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614208 alleles; AF 6.19e-07), supporting that it is very rare in population databases.2 In a calibrated BRCA2 functional study, this variant showed protein function similar to pathogenic control variants, and the ENIGMA BRCA2 functional table assigns PS3 at strong strength for p.Thr2722Ala.3 This missense change lies within the BRCA2 DNA-binding domain, has a BayesDel no-AF score of 0.396861 above the ENIGMA PP3 threshold of 0.30, and has low predicted splice impact by SpliceAI (maximum delta score 0.01).4
Final classification
Likely Pathogenic
PS3PP3PP5
BRCA2
c.8164A>G
p.Thr2722Ala
This variant
The BRCA2 c.8164A>G (p.Thr2722Ala) variant has not been observed in COSMIC and has been reported in ClinVar as Likely Pathogenic, including expert-panel review by ClinGen ENIGMA BRCA1/2.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 criteria-combination framework (CSPEC/VCEP override captured in final_classification_framework).
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA2 c.8164A>G
PS3 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗cspec ↗
4
cspec ↗bayesdelspliceai ↗
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_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 16 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
In a calibrated BRCA2 functional dataset, this variant was reported to show protein function similar to pathogenic control variants, and the ENIGMA BRCA2 Table 9 assigns PS3 at strong strength for c.8164A>G (p.Thr2722Ala). This supports a damaging effect on protein function.
Table 9 exact match: BRCA2 c.8164A>G p.(Thr2722Ala) -> PS3 Strong.Richardson 2021 listed as damaging.
PP3
supporting
Pathogenic
This missense variant lies within the BRCA2 DNA-binding domain and has a BayesDel no-AF score of 0.396861, which is above the ENIGMA PP3 threshold of 0.30. SpliceAI predicts low splice impact with a maximum delta score of 0.01, so the computational evidence supports a damaging protein effect rather than a splice effect.
Protein position 2722 is within the BRCA2 DNA-binding domain aa 2481-3186.BayesDel no-AF = 0.396861.SpliceAI max delta score = 0.01.
Assessed · not applied
· 8 not met · 8 not assessed
Pathogenic
PVS1
This variant is a missense substitution, not a nonsense, frameshift, or canonical +/-1,2 splice variant, and available data do not show an RNA-only loss-of-function effect.
PS1
No previously classified pathogenic or likely pathogenic variant with the same amino acid change or the same predicted splice effect was identified in the available evidence, so PS1 is not met.
PS4
Available evidence does not provide a case-control analysis or a quantitative demonstration that this variant is significantly enriched in affected individuals relative to controls, so PS4 cannot be assigned from the reviewed data.
PM2
This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614208 alleles; AF 6.19e-07), which is consistent with rarity.
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.
PP1
No segregation data were identified for this variant, so there is no quantitative likelihood ratio to support PP1.
PP4
No variant-specific clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified in the reviewed BRCA2 clinical-history resource, so PP4 was not assigned.
Benign
BA1
Population frequency does not meet the benign stand-alone threshold.
BS1
Population frequency does not meet the ENIGMA BS1 thresholds.
BS2
No evidence was identified to score this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA point-based BS2 framework, so BS2 was not assessed.
BS3
Available functional evidence does not support a benign effect.
BS4
No lack-of-segregation data or quantitative non-segregation likelihood ratio was identified for this variant, so BS4 was not assigned.
BP1
This missense variant is located within the BRCA2 DNA-binding domain, so it does not meet the ENIGMA BP1 rule, which is restricted to missense or similar variants outside clinically important functional domains with no predicted splice impact.
BP4
This variant does not meet the ENIGMA BP4 rule because it is a missense change in the BRCA2 DNA-binding domain and its BayesDel no-AF score is 0.396861, which is above the benign threshold of 0.18.
BP5
No variant-specific clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified in the reviewed BRCA2 clinical-history resource, so BP5 was not assigned.
BP7
This is a missense variant within a clinically important BRCA2 functional domain, and no benign RNA evidence was identified.
N/A · 9
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19499e-07; MAF= 0.00006%, 1/1614208 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47436e-07; MAF= 0.00008%, 1/1180030 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,208
0 hom
0 hom
European (non-Finnish) 1 / 1,180,030 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 479367)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.827. BayesDel score = 0.396861.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-bindin
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links