Classification rationale

PVS1PP3PP4PP5 Pathogenic

BRCA2 c.9117G>A

The BRCA2 c.9117G>A (p.Pro3039=) variant has been reported in ClinVar as Pathogenic with expert panel review.¹ This variant is rare in population databases, with AF 4.03e-06 (1/248378 alleles) in gnomAD v2.1 and AF 3.72e-06 (6/1613038 alleles) in gnomAD v4.1.² In a published RNA study, this variant caused exon 23 skipping in puromycin-treated lymphocytes, supporting an abnormal splicing effect consistent with loss of function.³ SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which supports a deleterious splicing effect.⁴ In the BRCA2-specific clinical-history likelihood dataset, this variant had an LR of 3.91 in 12 probands, meeting ENIGMA PP4 at supporting strength.⁵

PVS1 + PP3 + PP4 + PP5 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_pmid_22505045_houdayer_2012_hummutatvcep_specifications_table4_v1_2_2024_11_18cspec ↗

4 spliceai ↗cspec ↗

5 PMID:31853058 ↗vcep_pmid_31853058_brca2_clinical_history_lr

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

BRCA2 NM_000059.3

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

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= 3.71969e-06; MAF= 0.00037%, 6/1613038 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08708e-06; MAF= 0.00051%, 6/1179458 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.02612e-06; MAF= 0.00040%, 1/248378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.95576e-06; MAF= 0.00090%, 1/111660 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00037% · 6 / 1,613,038
0 hom · FAF 0.00018%

European (non-Finnish)

6 / 1,179,458

0.00051%

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

gnomAD v2.1

0.0004% · 1 / 248,378
0 hom

European (non-Finnish)

1 / 111,660

0.0009%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.89).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99061599, n = 1 times).

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:31853058

PMID PMID:31853058 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PP4 supports · met

PMID vcep_pmid_22505045_houdayer_2012_hummutat

PMID vcep_pmid_22505045_houdayer_2012_hummutat ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots