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 ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

BRCA2 NM_000059.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PS3 strong review Pathogenic

In the ENIGMA BRCA2 functional assay table, this exact variant, c.8375T>C (p.Leu2792Pro), is reported by two calibrated studies to show damaging protein function, and the table assigns PS3 at strong strength.

ENIGMA Table 9 exact-variant row for c.8375T>C / p.(Leu2792Pro)Assigned code PS3 StrongTwo calibrated studies reported damaging function

PMID:29884841 ↗cspec ↗

PP3 supporting review Pathogenic

This missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional domain defined by ENIGMA (amino acids 2481-3186). BayesDel is 0.54225, which is above the ENIGMA PP3 threshold of 0.30, and REVEL is also high at 0.931. SpliceAI predicts no significant splice effect (max delta 0.03), so the computational evidence supports a damaging protein effect rather than a splice mechanism.

Protein position 2792 lies within BRCA2 DNA-binding domainBayesDel 0.54225REVEL 0.931

cspec ↗spliceai ↗

PP5 supporting review Pathogenic

Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.

BRCA2 ENIGMA specification applicabilityClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 8 not met · 7 not assessed

Pathogenic

PVS1 This variant is a missense substitution, p.(Leu2792Pro), and does not fall into the BRCA2 null-variant or canonical splice categories used for PVS1.

PS1 No distinct previously classified pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available ClinVar evidence, so PS1 is not established.

PS4 No case-control analysis or other evidence showing statistically significant enrichment in affected individuals was identified for this variant, and no exact-variant entry was identified in the reviewed BRCA2 multifactorial/posterior tables for PS4 use.

PM2 This variant is absent from gnomAD v2.1, but it is present in gnomAD v4.1 at 1/1613924 alleles (AF 6.19608e-07; highest population AF 8.47529e-07 in European non-Finnish).

PM3 No evidence was identified showing this variant in trans with another BRCA2 pathogenic variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 cannot be assessed.

PP1 No quantitative co-segregation data were identified for this variant, and no exact-variant segregation likelihood ratio was identified in the reviewed BRCA2 multifactorial resources, so PP1 cannot be applied.

PP4 No exact-variant personal or family-history likelihood ratio was identified in the reviewed BRCA2 clinical-history table, so PP4 cannot be applied from the available multifactorial clinical data.

Benign

BA1 Available population data do not meet the ENIGMA BA1 threshold.

BS1 Available population data do not meet the ENIGMA BS1 thresholds.

BS2 No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that permits ENIGMA BS2 point assignment.

BS3 Available functional evidence does not support a benign effect.

BS4 No quantitative lack-of-segregation data were identified for this variant, and no exact-variant segregation likelihood ratio was identified in the reviewed BRCA2 multifactorial resources, so BS4 cannot be applied.

BP1 BP1_Strong is reserved for missense or silent variants outside clinically important BRCA2 domains with no predicted splice effect.

BP4 This variant is within the BRCA2 DNA-binding domain, but the computational results do not meet the benign thresholds.

BP5 No exact-variant personal or family-history likelihood ratio was identified in the reviewed BRCA2 clinical-history table, so BP5 cannot be applied from the available multifactorial clinical data.

N/A · 10 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7

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.

Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally va

PMID 29884841 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 strong

PMID 32444794

PMID 32444794 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 strong

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Check your email

Reset your password

Enter an access code

Your allowance