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LYFE SCIENCES
Project: HERA
NM_000059.3:c.8009C>G
p.Ser2670Trp  ·  BRCA2
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Classification rationale
1

The BRCA2 c.8009C>G (p.Ser2670Trp) variant has not been observed in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

clinvar ↗ cspec ↗
2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls and meeting PM2_Supporting under the BRCA2 VCEP framework.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In the BRCA2 VCEP functional assay table, this variant is recorded with splice alteration evidence including exon 18 deletion, but the reviewed evidence was not accepted for PS3 or BS3 code application, so neither functional criterion is met from the available curated data.

cspec ↗
4

For computational evidence, REVEL is 0.825, but the BRCA2 VCEP rule uses BayesDel and SpliceAI; BayesDel no-AF is 0.159332 and SpliceAI max delta score is 0.03, which supports BP4 and does not meet PP3 thresholds.

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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 489785)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
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 = 0.03). REVEL score = 0.825. BayesDel score = 0.159332.
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.
ResidueS2670
Hotspots ↗