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LYFE SCIENCES
Project: HERA
NM_000059.4:c.8149G>T
p.Ala2717Ser  ·  BRCA2
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Classification rationale
1

The BRCA2 c.8149G>T (p.Ala2717Ser) variant has been observed in somatic cancers in COSMIC (COSV66460731, n=3) and has also been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as benign.

clinvar ↗
2

This variant is common in population databases, with gnomAD v2.1 group-maximum filter allele frequency 0.00162114 and gnomAD v4.1 group-maximum filter allele frequency 0.00163682, both above the ENIGMA BA1 threshold of 0.001.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Calibrated BRCA2 functional evidence supports a benign effect: ENIGMA Table 9 assigns BS3 Strong based on three studies showing function similar to benign controls, with no aberrant RNA result listed.

cspec ↗
4

SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.03, which argues against splice disruption.

spliceai ↗
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
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Gaps remaining
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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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Neutral
OncoKB classifies this variant as Likely Neutral; biological effect: Likely Neutral.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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 ↗