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LYFE SCIENCES
Project: HERA
NM_000059.3:c.5946del
p.Ser1982ArgfsTer22  ·  BRCA2
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Classification rationale
1

The BRCA2 c.5946del (p.(Ser1982ArgfsTer22)) variant has been observed in somatic cancers in COSMIC (COSV66447676, n=10) and has been reported in ClinVar as pathogenic with expert-panel review by the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.

clinvar ↗ PMID:10417300 ↗ PMID:11466700 ↗
2

This variant is present in population databases, including gnomAD v2.1 at AF 0.000276509 (78/282088 alleles) and gnomAD v4.1 at AF 0.000139416 (225/1613878 alleles), with highest frequency in the Ashkenazi Jewish population; therefore it is not absent from controls and does not meet PM2.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Clinical-history evidence supports pathogenicity: in the BRCA2 likelihood-ratio dataset, c.5946delT has an LR of 31.79 from 149 probands, exceeding the ENIGMA PP4_Strong threshold of 18.7.

PMID:31853058 ↗ cspec ↗
4

Computational and predicted consequence data show a frameshift leading to p.(Ser1982ArgfsTer22), while SpliceAI predicts no additional splice alteration (max delta 0.00); under the BRCA2 ENIGMA exon-specific truncating-variant framework, exon 11 supports PVS1 and PM5_Strong for this protein-truncating variant.

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
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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= 0.000276509; MAF= 0.02765%, 78/282088 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00588576; MAF= 0.58858%, 61/10364 alleles, homozygotes = 0); grpmax FAF= 5.39e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.000139416; MAF= 0.01394%, 225/1613878 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00533856; MAF= 0.53386%, 158/29596 alleles, homozygotes = 0); grpmax FAF= 2.154e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (67 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 9325)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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; COSV66447676, n = 10 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueS1982
Hotspots ↗