The BRCA2 c.7685T>G (p.Phe2562Cys; p.F2562C) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as likely pathogenic.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.2 In a calibrated BRCA2 functional study summarized by the ENIGMA functional assay table, this variant showed protein function similar to pathogenic control variants, supporting PS3_Strong.3 This missense change lies in the BRCA2 DNA-binding domain; BayesDel no-AF is 0.421539, which is above the ENIGMA PP3 threshold of 0.30, REVEL is 0.921, and SpliceAI predicts little splice effect with a maximum delta score of 0.01.4 In the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 0.9916 in 1 proband, which is within the neutral zone and does not support PP4 or BP5.5
Final classification
Likely Pathogenic
PM2PP5PS3PP3
BRCA2
c.7685T>G
p.Phe2562Cys
This variant
The BRCA2 c.7685T>G (p.Phe2562Cys; p.F2562C) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as likely pathogenic.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 Table 3 final-classification framework (CSPEC/VCEP override).
Classification rationale
PM2PP5PS3PP3
Likely Pathogenic
BRCA2 c.7685T>G
PM2 + PP5 + PS3 + PP3
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗cspec ↗
4
bayesdelrevelspliceai ↗cspec ↗
5
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗cspec ↗
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 · 4 applied · 13 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
In a calibrated BRCA2 functional study summarized in the ENIGMA functional assay table, this variant showed protein function similar to pathogenic control variants, and the ENIGMA resource assigns PS3 at strong strength.
ENIGMA Table 9 row for c.7685T>GPS3 Strong assignment
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity in population controls and supports PM2 at supporting strength under the ENIGMA BRCA2 framework.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PP3
supporting
review
Pathogenic
This missense variant lies in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.421539, which is above the ENIGMA PP3 threshold of 0.30. REVEL is also high at 0.921, while SpliceAI is low at 0.01, supporting a damaging protein effect rather than a splice effect; together these findings support PP3 at supporting strength.
BRCA2 DNA-binding domain locationBayesDel no-AF 0.421539REVEL 0.921
Assessed · not applied
· 7 not met · 6 not assessed
Pathogenic
PS1
No evidence was identified that a previously classified pathogenic or likely pathogenic variant causes the same amino acid change or the same splicing effect, so PS1 cannot be assessed from the available evidence.
PS4
No case-control dataset or other quantitative evidence was identified showing that this variant is significantly enriched in affected individuals compared with controls, so PS4 cannot be assessed.
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 cannot be assessed.
PP1
No segregation data were identified to show co-segregation of this variant with disease in affected relatives, so PP1 cannot be assessed from the available evidence.
PP4
In the BRCA2 clinical-history likelihood-ratio resource, this variant has an LR of 0.9916 in 1 proband.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not approach the ENIGMA BRCA2 BA1 threshold of filter allele frequency greater than 0.001.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BRCA2 BS1 frequency threshold of filter allele frequency greater than 0.00002 for supporting or greater than 0.0001 for strong benign evidence.
BS2
No qualifying evidence was identified showing this variant in individuals without a Fanconi anemia phenotype under the ENIGMA BRCA2 BS2 scoring framework, so BS2 cannot be assessed.
BS3
Available calibrated functional evidence does not show normal protein function.
BS4
No quantitative non-segregation data were identified to show lack of segregation with disease in affected relatives, so BS4 cannot be assessed.
BP1
This missense variant is within the BRCA2 DNA-binding domain at residue 2562, and ENIGMA applies BP1_Strong only to silent, missense, or in-frame variants outside clinically important domains with no predicted splice effect.
BP4
This missense variant is in the BRCA2 DNA-binding domain (amino acids 2481-3186), where ENIGMA applies BP4 only when BayesDel no-AF is less than or equal to 0.18 and SpliceAI is less than or equal to 0.1.
BP5
In the BRCA2 clinical-history likelihood-ratio resource, this variant has an LR of 0.9916 in 1 proband.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 142784)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.921. BayesDel score = 0.421539.
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