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LYFE SCIENCES
Project: HERA
NM_000059.3:c.8149G>T
p.Ala2717Ser  ·  BRCA2
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Classification rationale
1

The BRCA2 c.8149G>T (p.Ala2717Ser) variant has been reported in ClinVar as Benign with expert panel review, and curated cancer resources did not identify it as a statistically significant hotspot while OncoKB describes it as likely neutral.

clinvar ↗ hotspots ↗ oncokb ↗
2

This variant is present in population databases at a frequency above the BRCA2 ENIGMA BA1 threshold, with grpmax filtering allele frequency 0.00162114 in gnomAD v2.1 and 0.00163682 in gnomAD v4.1, supporting a benign population interpretation.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In curated BRCA2 functional studies, this variant showed protein function similar to benign control variants, and associated RNA data showed no aberrant splicing, supporting BS3_Strong.

cspec ↗
4

Computational evidence does not support a damaging interpretation under the BRCA2 ENIGMA rules: the BayesDel no-AF score is -0.0816274, REVEL is 0.535, and no SpliceAI score demonstrating splice impact was identified, so PP3 is not met and BP4 could not be fully applied.

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
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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= 0.00111433; MAF= 0.11143%, 315/282680 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00207814; MAF= 0.20781%, 15/7218 alleles, homozygotes = 0); grpmax FAF= 0.00162114.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.00139272; MAF= 0.13927%, 2248/1614110 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00169915; MAF= 0.16992%, 2005/1180000 alleles, homozygotes = 2); grpmax FAF= 0.00163682.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (22 clinical laboratories) and as Likely benign (11 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 41564)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.535. BayesDel score = -0.0816274.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66460731, n = 3 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA2717
Hotspots ↗