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LYFE SCIENCES
Project: HERA
NM_000059.3:c.2471T>C
p.Leu824Ser  ·  BRCA2
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Classification rationale
1

The BRCA2 c.2471T>C (p.Leu824Ser) variant has not been observed in COSMIC and has been reported in ClinVar, where the current expert-panel classification is likely benign.

clinvar ↗
2

This variant is present at low frequency in population databases, including 2/237562 alleles in gnomAD v2.1 and 4/1602664 alleles in gnomAD v4.1, with v2.1 grpmax FAF 1.975e-05 and v4.1 grpmax FAF 2.98e-05; these values are below the ENIGMA BA1 and BS1 thresholds and do not support PM2 because the variant is not absent from controls.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Computational evidence supports a benign interpretation under the BRCA2 ENIGMA framework because p.Leu824Ser lies outside the BRCA2 clinically important domains used for missense evaluation, SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, BayesDel is -0.270943, and REVEL is 0.261, supporting BP1_Strong and not supporting PP3.

cspec ↗ spliceai ↗
4

The BRCA2 clinical-history likelihood ratio is 0.60 in 2 probands, which falls in the neutral zone and does not support either PP4 or BP5.

cspec ↗ PMID:31853058 ↗
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= 8.41885e-06; MAF= 0.00084%, 2/237562 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000113507; MAF= 0.01135%, 2/17620 alleles, homozygotes = 0); grpmax FAF= 1.975e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.49584e-06; MAF= 0.00025%, 4/1602664 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 8.92379e-05; MAF= 0.00892%, 4/44824 alleles, homozygotes = 0); grpmax FAF= 2.98e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely 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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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). REVEL score = 0.261. BayesDel score = -0.270943.
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.
ResidueL824
Hotspots ↗