Starting

Initialising…

BRCA2

Final classification

Likely Pathogenic

BRCA2 c.8375T>C · p.Leu2792Pro

BRCA2

The BRCA2 c.8375T>C (p.Leu2792Pro) variant has been reported in ClinVar, including a Likely Pathogenic expert-panel classification from ClinGen ENIGMA.

Gene

BRCA2

Transcript

NM_000059.3

HGVS · transcript:coding

NM_000059.3:c.8375T>C

Consequence

N/A

GRCh38

chr13:32370445 T>C

GRCh37

chr13:32944582 T>C

Basis ENIGMA BRCA1 and BRCA2 Specification v1.2 official final-classification framework was used, applying the Table 3 criteria-combination rules captured in final_classification_framework. ▾

ENIGMA BRCA1 and BRCA2 Specification v1.2 official final-classification framework was used, applying the Table 3 criteria-combination rules captured in final_classification_framework.

Classification rationale

PS3PP3PP5 Likely Pathogenic

BRCA2 c.8375T>C

The BRCA2 c.8375T>C (p.Leu2792Pro) variant has been reported in ClinVar, including a Likely Pathogenic expert-panel classification from ClinGen ENIGMA.¹ This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1613924 alleles; AF 6.19608e-07), supporting rarity but not strict absence across available population datasets.² In the ENIGMA BRCA2 curated functional dataset, two calibrated studies showed damaging protein function for this exact variant, and Table 9 assigns PS3 at strong strength.³ In silico data support a damaging protein effect within the BRCA2 DNA-binding domain, with BayesDel 0.54225 and REVEL 0.931, while SpliceAI predicts no significant splice impact (max delta 0.03).⁴

PS3 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_specifications_table9_v1_2_2024_11_18PMID:29884841 ↗cspec ↗

4 bayesdelrevelspliceai ↗cspec ↗

Gene diagram · NM_000059.3 · variants mapped to exon structure

BRCA2 NM_000059.3

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19608e-07; MAF= 0.00006%, 1/1613924 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47529e-07; MAF= 0.00008%, 1/1179900 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,924
0 hom

European (non-Finnish)

1 / 1,179,900

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.931. BayesDel score = 0.54225.

SpliceAI ↗

Functional 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 ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

PMID PMID:29884841

PMID PMID:29884841 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

PMID PMID:32444794

PMID PMID:32444794 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots