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

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 · 4 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 · 4

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

This synonymous variant affects the last nucleotide of exon 23. In a published RNA study using puromycin-treated lymphocytes, this variant caused exon 23 skipping. Exon 23 is 164 nucleotides long, so complete skipping is out of frame, and ENIGMA Table 4 assigns exon 23 loss/spliceogenic RNA events to PVS1/PVS1(RNA). Because BRCA2 loss of function is an established disease mechanism, this supports PVS1 at very strong strength.

BRCA2 loss of function established in gene-specific frameworkRNA study reported exon 23 skipping for c.9117G>AExon 23 annotated as PVS1/PVS1(RNA)-eligible in ENIGMA Table 4

cspec ↗

PP3 supporting Pathogenic

Computational splicing evidence supports a deleterious splice effect. SpliceAI predicts strong splice disruption with a maximum delta score of 0.89, which is above the ENIGMA PP3 threshold of 0.2 for predicted splicing impact in silent variants.

SpliceAI max delta 0.89

cspec ↗spliceai ↗

PP4 supporting Pathogenic

Clinical-history likelihood analysis supports pathogenicity. In the BRCA2-specific Li et al. dataset, this variant had an LR of 3.91 in 12 probands, which is above the ENIGMA PP4 Supporting threshold of 2.08 and below the Moderate threshold of 4.3.

Clinical-history LR 3.910369863346765N probands 12

PMID:31853058 ↗

PP5 supporting Pathogenic

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

CSPEC applicability statementClinVar expert panel classification

cspec ↗clinvar ↗

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

Pathogenic

PS1 Available evidence confirms abnormal splicing for this variant, but the reviewed materials do not establish a same-effect reference pathogenic variant under the ENIGMA PS1 splicing framework strongly enough to assign PS1 here.

PS3 RNA studies showed exon 23 skipping, but ENIGMA directs mRNA-only damaging evidence to PVS1(RNA) rather than PS3.

PS4 This variant has been reported in affected individuals and appears in the ENIGMA reference-set materials with a very high posterior probability, but the reviewed materials do not provide a qualifying case-control odds ratio and p-value meeting the ENIGMA PS4 rule.

PM2 This variant is not absent from controls.

PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia, so PM3 was not assessed.

PP1 No quantitative co-segregation likelihood ratio for this exact variant was identified in the reviewed materials, so PP1 was not assessed.

Benign

BA1 Population frequency does not meet the ENIGMA BA1 threshold.

BS1 Population frequency does not meet the ENIGMA BS1 threshold.

BS2 No informative evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia at a level that would satisfy the ENIGMA BS2 point-based framework.

BS3 Available functional evidence does not support a benign effect.

BS4 No quantitative lack-of-segregation likelihood ratio for this exact variant was identified in the reviewed materials, so BS4 was not assessed.

BP1 This silent variant does not meet ENIGMA BP1_Strong because predicted splice impact is present.

BP4 This silent variant does not meet BP4 because ENIGMA requires no predicted splice impact for a silent variant in a clinically important functional domain, with SpliceAI at or below 0.1.

BP5 Clinical-history likelihood analysis does not support a benign interpretation.

BP7 This silent variant does not meet BP7.

N/A · 9 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6

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 22505045

PMID 22505045 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 very strong

Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model

PMID 31853058 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PP4 supporting

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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