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.1 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.2 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 PP3.3 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 BP5.4
Final classification
Likely Benign
BP1BP6
BRCA2
c.2471T>C
p.Leu824Ser
This variant
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.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework from the official CSPEC/VCEP source.
Classification rationale
BP1BP6
Likely Benign
BRCA2 c.2471T>C
BP1 + BP6
→
Likely Benign
3
cspec ↗spliceai ↗bayesdelrevel
4
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗
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_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 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
Benign
This missense variant is outside the BRCA2 clinically important domains used by the ENIGMA specification, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is at or below the BP1_Strong threshold of 0.1. These findings support BP1_Strong.
Protein consequence p.(Leu824Ser) at residue 824.Residue 824 is outside BRCA2 PALB2 binding domain aa10-40 and DNA binding region aa2481-3186.SpliceAI max delta score 0.01 (≤0.1).
Assessed · not applied
· 15 not met · 3 not assessed
Pathogenic
PVS1
This missense variant does not fall into the BRCA2 PVS1 null-variant categories, and no RNA evidence showing a loss-of-function transcript effect was identified.
PS1
No same-amino-acid pathogenic or likely pathogenic comparator variant was verified for this amino acid change, so PS1 was not assessed from the available evidence.
PS3
No calibrated functional study result for BRCA2 p.(Leu824Ser) was identified in the reviewed BRCA2 functional resources, so available evidence does not support PS3.
PS4
Available evidence does not show a statistically significant enrichment of this variant in affected individuals compared with controls, so PS4 is not met.
PM2
This variant is present in population databases, so it is not absent from controls.
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 assessed.
PM5
This is a missense variant rather than a protein-truncating variant, and the BRCA2 ENIGMA PM5 rule in the reviewed materials is the PM5_PTC framework for qualifying truncating variants.
PP1
No quantitative co-segregation data were identified for this variant, so available evidence does not support PP1.
PP3
Computational evidence does not meet the BRCA2 ENIGMA PP3 thresholds.
PP4
The BRCA2 clinical-history likelihood ratio for this variant is 0.60 in 2 probands, which is below the ENIGMA PP4 supporting threshold of 2.08.
Benign
BA1
Population frequency does not reach the BRCA2 ENIGMA BA1 threshold.
BS1
Population frequency does not meet the BRCA2 ENIGMA BS1 threshold in the reviewed evidence.
BS2
No point-based evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 framework, so BS2 was not assessed.
BS3
No calibrated benign functional result for BRCA2 p.(Leu824Ser) was identified in the reviewed BRCA2 functional resources, so available evidence does not support BS3.
BS4
No quantitative lack-of-segregation evidence was identified for this variant, so available evidence does not support BS4.
BP4
Although computational predictors do not suggest a damaging effect, BP4 is not applied here because the BRCA2 ENIGMA missense BP4 rule is restricted to variants inside the specified clinically important domains.
BP5
The BRCA2 clinical-history likelihood ratio for this variant is 0.60 in 2 probands, which is above the ENIGMA BP5 supporting threshold of 0.48.
BP7
This is a missense variant, and no RNA study demonstrating a benign transcript effect was identified.
N/A · 8
PS2 · PM1 · PM4 · PM6 · PP2 · PP5 · BP2 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,602,664
0 hom · FAF 0.003%
0 hom · FAF 0.003%
East Asian 4 / 44,824 |
0.0089% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.00084%
· 2 / 237,562
0 hom · FAF 0.002%
0 hom · FAF 0.002%
East Asian 2 / 17,620 |
0.011% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.261. BayesDel score = -0.270943.
Functional
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.
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