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LYFE SCIENCES
Project: HERA
NM_000059.4:c.663T>G
p.Phe221Leu  ·  BRCA2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

No calibrated ENIGMA functional assay result for this specific variant was identified in the curated BRCA2 functional dataset, so functional evidence was not applied.

cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueF221
Hotspots ↗