The BRCA2 c.9117G>A (p.(Pro3039=), p.(P3039=)) variant has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification from the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.1 This variant is rare in population databases but is not absent from controls, with 1/248378 alleles in gnomAD v2.1 (AF 0.00000403) and 6/1613032 alleles in gnomAD v4.1 (AF 0.00000372), so PM2 is not met and BA1/BS1 thresholds are not reached.2 Clinical-history likelihood-ratio analysis for BRCA2 c.9117G>A showed LR 3.91 in 12 probands, which exceeds the ENIGMA PP4 supporting threshold of 2.08 and supports PP4 at supporting strength.3 SpliceAI predicts a strong splice effect for this synonymous variant, with a maximum delta score of 0.89, which is above the ENIGMA PP3 threshold of 0.20 for predicted splicing impact and argues against BP4/BP7.4
Final classification
VUS
PP3PP4PP5
BRCA2
c.9117G>A
p.Pro3039=
This variant
The BRCA2 c.9117G>A (p.(Pro3039=), p.(P3039=)) variant has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification from the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.
Applied the official ClinGen ENIGMA BRCA1/2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules (ACMG/AMP 2015 with ENIGMA Table 3 adaptations).
Classification rationale
PP3PP4PP5
VUS
BRCA2 c.9117G>A
PP3 + PP4 + PP5
→
VUS
3
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗cspec ↗
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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 · 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
PP3
supporting
Pathogenic
SpliceAI predicts a strong splice effect for this synonymous variant, with a maximum delta score of 0.89, which is above the BRCA2 ENIGMA PP3 threshold of 0.20 for predicted splicing impact. This supports PP3 at supporting strength.
SpliceAI DS_AL 0.82DS_DL 0.89max delta score 0.89.
PP4
supporting
Pathogenic
Clinical-history likelihood-ratio analysis for BRCA2 c.9117G>A showed LR 3.91 in 12 probands, which is above the ENIGMA PP4 supporting threshold of 2.08 and below the moderate threshold of 4.3. This supports PP4 at supporting strength.
Li 2020 BRCA2 clinical-history table: HGVS_Nucleotide c.9117G>AN_Probands 12LR 3.910369863346765.
Assessed · not applied
· 8 not met · 8 not assessed
Pathogenic
PVS1
This synonymous variant does not fall into the default null-variant categories for PVS1, and no direct mRNA assay evidence was identified here to show a proven loss-of-function transcript effect.
PS1
No same-amino-acid-change comparator or same proven splice-effect pathogenic comparator was identified here for this variant, so PS1 was not applied.
PS3
No calibrated protein functional assay result for BRCA2 c.9117G>A was identified in the reviewed BRCA2 functional table, so PS3 was not applied.
PS4
This variant has been reported in affected individuals and is listed as pathogenic in expert-curated resources, but no case-control analysis meeting the BRCA2 PS4 rule was identified here.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not applied.
PP1
No quantitative co-segregation likelihood ratio was identified for this variant, so PP1 was not applied.
Benign
BA1
The observed population frequency is well below the ENIGMA BA1 threshold.
BS1
The observed population frequency does not reach the ENIGMA BS1 thresholds.
BS2
No point-based evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia as required by the BRCA2 ENIGMA BS2 rule, so BS2 was not applied.
BS3
No calibrated benign functional assay result for BRCA2 c.9117G>A was identified in the reviewed BRCA2 functional table, so BS3 was not applied.
BS4
No quantitative lack-of-segregation likelihood ratio was identified for this variant, so BS4 was not applied.
BP1
This synonymous variant lies within the BRCA2 DNA-binding region (amino acids 2481-3186), and SpliceAI predicts splice impact with a maximum delta score of 0.89.
BP4
For a silent variant in a clinically important BRCA2 domain, BP4 requires no predicted splice impact with SpliceAI at or below 0.10.
BP5
Clinical-history likelihood-ratio analysis for BRCA2 c.9117G>A showed LR 3.91 in 12 probands, which is above the benign BP5 threshold of 0.48 and therefore does not support BP5.
BP7
This is a silent variant within the BRCA2 DNA-binding domain, but BP7 for this setting requires BP4 to be met, and BP4 is not met because SpliceAI predicts strong splice impact with a maximum delta score of 0.89.
N/A · 9
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.71969e-06; MAF= 0.00037%, 6/1613038 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08708e-06; MAF= 0.00051%, 6/1179458 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.02612e-06; MAF= 0.00040%, 1/248378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.95576e-06; MAF= 0.00090%, 1/111660 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,613,038
0 hom · FAF 0.00018%
0 hom · FAF 0.00018%
European (non-Finnish) 6 / 1,179,458 |
0.00051% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 248,378
0 hom
0 hom
European (non-Finnish) 1 / 111,660 |
0.0009% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.89).
Functional
Unknown Oncogenic Effect
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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; COSV99061599, n = 1 times).
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.
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→PP4
supporting
Sources & reference links