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LYFE SCIENCES
Project: HERA
NM_000059.3:c.7970A>C
p.Lys2657Thr  ·  BRCA2
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Classification rationale
1

The BRCA2 c.7970A>C (p.Lys2657Thr, K2657T) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance and other submitters reported likely pathogenic and uncertain significance assertions.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1614028 alleles overall; highest observed frequency 1/59996 in Admixed American individuals), supporting rarity but not complete absence from population databases.

gnomad_v2 ↗ gnomad_v4 ↗
3

In a calibrated BRCA2 functional study summarized by the ENIGMA BRCA1/2 specification, p.Lys2657Thr showed protein function similar to pathogenic control variants, supporting PS3 at strong strength.

cspec ↗ PMID:33609447 ↗
4

Computational evidence predicts no significant splice impact (SpliceAI max delta score 0.01), while the missense prediction profile is mixed under ENIGMA thresholds (REVEL 0.799; BayesDel 0.270216), so PP3 and BP4 are not independently met.

cspec ↗ spliceai ↗
5

A BRCA2 clinical-history likelihood ratio of 1.188967663938105 from 1 proband falls in the ENIGMA neutral zone (>0.48 and <2.08), so neither PP4 nor BP5 is supported by the reviewed multifactorial clinical-history data.

cspec ↗ PMID:31853058 ↗
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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.19568e-07; MAF= 0.00006%, 1/1614028 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66678e-05; MAF= 0.00167%, 1/59996 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.799. BayesDel score = 0.270216.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueK2657
Hotspots ↗