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
BRCA2
Final classification
Likely benign
BRCA2 c.663T>G · p.Phe221Leu
BRCA2
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 ↗
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
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.
PMID cspec
Found
Structured finding pending for this record — see source link.
Applied to
→BP1 supports · met
→BP6 supports · met
PMID spliceai
Found
Structured finding pending for this record — see source link.
Applied to
→BP1 supports · met
Sources & reference links