The BRCA2 c.663T>G (p.Phe221Leu, p.F221L) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classified it as likely benign.1 This variant is present at very low frequency in population databases, including gnomAD v2.1 at 1/245048 alleles (AF 4.08e-06) and gnomAD v4.1 at 5/1598264 alleles (AF 3.13e-06; grpmax FAF 4.45e-06), which is below ENIGMA BS1/BA1 thresholds and means the variant is not absent from controls for PM2_Supporting.2 No calibrated ENIGMA functional assay result for this specific variant was identified in the curated BRCA2 functional dataset, so functional evidence was not applied.3 This missense change occurs outside the BRCA2 PALB2-binding and DNA-binding domains used for ENIGMA missense protein interpretation, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, supporting BP1_Strong.4
Final classification
Likely benign
BP1BP6
BRCA2
c.663T>G
p.Phe221Leu
This variant
The BRCA2 c.663T>G (p.Phe221Leu, p.F221L) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classified it as likely benign.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official CSPEC/VCEP framework; ACMG/AMP 2015 with ENIGMA Table 3 adaptations).
Classification rationale
BP1BP6
Likely benign
BRCA2 c.663T>G
BP1 + BP6
→
Likely benign
3
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
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 · 14 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
BP1
strong
review
Benign
This missense variant affects codon 221, which is outside the BRCA2 clinically important domains used by ENIGMA, and SpliceAI predicts no significant splice effect with a max delta score of 0.01, which is below the no-splicing threshold of 0.10. This supports BP1_Strong.
Protein position 221 is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding region (aa 2481-3186).SpliceAI max delta score = 0.01below the ≤0.10 threshold.
Assessed · not applied
· 7 not met · 7 not assessed
Pathogenic
PS1
No same-amino-acid pathogenic or likely pathogenic BRCA2 variant acting through the same predicted mechanism was identified from the available evidence, so PS1 was not assessed.
PS3
No calibrated BRCA2 functional assay result for this specific variant was identified in the curated ENIGMA functional dataset, so PS3 was not assessed.
PS4
Available evidence does not show a statistically significant enrichment of this variant in affected individuals compared with controls.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified for biallelic BRCA2 disease, Fanconi anemia phenotype, or qualifying trans observations for this variant, so PM3 was not assessed.
PP1
No quantitative co-segregation result was identified for this variant, so PP1 was not assessed.
PP3
Available predictive evidence does not support PP3.
PP4
The BRCA2 clinical-history likelihood ratio for this variant is 0.67 in 6 probands, which is below the ENIGMA PP4 threshold of 2.08.
Benign
BA1
This variant does not reach the ENIGMA BA1 threshold.
BS1
Population frequency is below the ENIGMA BS1 thresholds.
BS2
No point-based evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia, so BS2 was not assessed.
BS3
No calibrated benign functional assay result for this specific variant was identified in the curated ENIGMA functional dataset, so BS3 was not assessed.
BS4
No quantitative lack-of-segregation likelihood ratio was identified for this variant, so BS4 was not assessed.
BP5
The BRCA2 clinical-history likelihood ratio for this variant is 0.67 in 6 probands, which is above the ENIGMA BP5 threshold of 0.48.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.12839e-06; MAF= 0.00031%, 5/1598264 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.68039e-05; MAF= 0.00268%, 2/74616 alleles, homozygotes = 0); grpmax FAF= 4.45e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.08083e-06; MAF= 0.00041%, 1/245048 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.03228e-06; MAF= 0.00090%, 1/110714 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,598,264
0 hom · FAF 0.00044%
0 hom · FAF 0.00044%
African/African American 2 / 74,616 |
0.0027% |
European (non-Finnish) 3 / 1,167,478 |
0.00026% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.00041%
· 1 / 245,048
0 hom
0 hom
European (non-Finnish) 1 / 110,714 |
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 Uncertain significance (8 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Likely Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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.
Sources & reference links