Starting

Initialising…

BRCA2

Final classification

Benign

BRCA2 c.4071A>C · p.Leu1357=

BRCA2

BRCA2 ENIGMA BA1 is met because the variant exceeds the stand-alone benign frequency threshold in gnomAD: v2.1 grpmax FAF 0.00161392 and v4.1 grpmax FAF 0.00154091, both >0.001.

Gene

BRCA2

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.4071A>C

Consequence

N/A

GRCh38

chr13:32338426 A>C

GRCh37

chr13:32912563 A>C

Basis ENIGMA BRCA2 ACMG/AMP v1.2 qualitative classification. BA1 (Stand Alone) is sufficient for Benign; BS1 (Strong) and BP1_Strong are concordant additional benign evidence. ▾

ENIGMA BRCA2 ACMG/AMP v1.2 qualitative classification. BA1 (Stand Alone) is sufficient for Benign; BS1 (Strong) and BP1_Strong are concordant additional benign evidence.

Classification rationale

BA1BS1BP1 Benign

BRCA2 c.4071A>C

BRCA2 ENIGMA BA1 is met because the variant exceeds the stand-alone benign frequency threshold in gnomAD: v2.1 grpmax FAF 0.00161392 and v4.1 grpmax FAF 0.00154091, both >0.001.¹ The variant is synonymous, p.(Leu1357=), and lies outside the BRCA2 clinically important domains defined by ENIGMA; with SpliceAI max delta score 0.00, this satisfies BP1_Strong.² ClinVar shows a concordant benign expert-panel assertion from ENIGMA, which supports but does not replace the VCEP rule-based classification.³

BA1 + BS1 + BP1 → Benign

1 gnomad_v2 ↗

2 cspec ↗

3 clinvar ↗

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

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 benign

gnomAD v4.1

gnomAD v2.1

Allele frequency by ancestry

three datasets · side by side

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

Literature · how each cited paper was used

4papers cited

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

PMID cspec

PMID cspec ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BA1 supports · met →BP1 supports · met →BS1 supports · met

PMID gnomad_v2

PMID gnomad_v2 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BA1 supports · met →BS1 supports · met

PMID gnomad_v4

PMID gnomad_v4 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BA1 supports · met →BS1 supports · met

PMID spliceai

PMID spliceai ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP1 supports · met

Sources & reference links

6Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB