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LYFE SCIENCES
Project: HERA
NM_000059.4:c.5350_5351del
p.Asn1784HisfsTer2  ·  BRCA2
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Classification rationale
1

The BRCA2 NM_000059.4:c.5350_5351del (NP_000050.3:p.(Asn1784HisfsTer2); p.(N1784Hfs*2)) variant has been reported in ClinVar with an expert-panel Pathogenic classification, and curated somatic review resources describe it as a likely loss-of-function BRCA2 alteration.

clinvar ↗ oncokb ↗
2

This variant is present in population databases at low frequency, including 1/31,198 alleles in gnomAD v2.1 (AF 3.20533e-05) and 41/1,612,540 alleles in gnomAD v4.1 (AF 2.54257e-05; grpmax FAF 2.315e-05), which is too high for PM2 but far below BA1.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

The variant is a frameshift deletion predicted to truncate BRCA2 after codon 1784, and the ENIGMA BRCA2 exon-level table designates exon 11 as eligible for full-strength PVS1 and PM5_Strong (PTC).

cspec ↗
4

Clinical-history modeling for BRCA2 reports a likelihood ratio of 812.95 from 42 probands, exceeding the ENIGMA Very Strong PP4 threshold of 350; SpliceAI shows no separate splice signal (max delta 0.00).

PMID:31853058 ↗ 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
—
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= 3.20533e-05; MAF= 0.00321%, 1/31198 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.52912e-05; MAF= 0.00653%, 1/15316 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.54257e-05; MAF= 0.00254%, 41/1612540 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.80507e-05; MAF= 0.00481%, 3/62434 alleles, homozygotes = 0); grpmax FAF= 2.315e-05.
gnomAD CanadaAbsent from gnomAD-Canada v1.0.
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (35 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 37959)
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; COSV104701329, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueN1784
Hotspots ↗