Classification rationale

PS3PM2PP5 Likely Pathogenic

BRCA2 c.9227G>T

The BRCA2 c.9227G>T (p.Gly3076Val) variant has not been observed in COSMIC and has been reported in ClinVar, where the overall classification is Pathogenic with expert panel review by the ClinGen ENIGMA BRCA1/BRCA2 Variant Curation Expert Panel.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.² A calibrated BRCA2 functional assay summarized in ENIGMA Table 9 supports a damaging effect on protein function, and this evidence meets PS3 at Strong strength.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07, which is below the ENIGMA PP3 splice threshold of 0.20 and below the BP4 splice threshold of 0.10.⁴

PS3 + PM2 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_specifications_table9_v1_2_2024_11_18cspec ↗

4 spliceai ↗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_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

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 Pathogenic

This variant has a calibrated BRCA2 functional assay result showing a damaging effect on protein function. ENIGMA Table 9 assigns PS3 Strong for c.9227G>T (p.Gly3076Val).

Specifications Table 9 lists BRCA2 c.9227G>T p.(Gly3076Val) as PS3 Strong.The table notes one calibrated study reporting protein function similar to pathogenic control variants.

cspec ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports rarity in population databases and is consistent with PM2_Supporting.

gnomAD v2.1: absent.gnomAD v4.1: absent.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP5 supporting Pathogenic

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

The ENIGMA BRCA2 CSPEC marks PP5 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

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

Pathogenic

PVS1 This variant is a missense change, NM_000059.4:c.9227G>T (p.Gly3076Val, p.G3076V), and does not fall into the BRCA2 null-variant categories used for PVS1.

PS1 No previously established pathogenic BRCA2 variant producing the same amino acid substitution was identified in the reviewed sources, so PS1 was not adjudicated from the available evidence.

PS4 No case-control comparison or quantified enrichment in affected individuals versus controls was identified from the available evidence, so PS4 was not adjudicated.

PM3 No evidence was identified for this variant in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not adjudicated.

PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not adjudicated.

PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.07), which is below the ENIGMA PP3 splice threshold of 0.20.

PP4 The BRCA2 clinical-history likelihood ratio for this variant is 0.776 in 1 proband, which is below the PP4 supporting threshold of 2.08.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the BA1 stand-alone benign threshold of FAF greater than 0.001.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below both the BS1 supporting threshold of FAF greater than 0.00002 and the BS1 strong threshold of FAF greater than 0.0001.

BS2 No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified to score BS2.

BS3 Available calibrated functional evidence shows a damaging effect on BRCA2 protein function rather than normal function, so BS3 is not met.

BS4 No quantitative evidence showing lack of segregation with disease was identified for this variant, so BS4 was not adjudicated.

BP1 This missense variant affects residue 3076 within the BRCA2 DNA-binding region (amino acids 2481-3186), so it is not outside a clinically important functional domain.

BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.07, below the BP4 splice threshold of 0.10), but ENIGMA BP4 for a missense variant inside a clinically important domain also requires BayesDel no-AF less than or equal to 0.18 and no predicted impact via protein change.

BP5 The BRCA2 clinical-history likelihood ratio for this variant is 0.776 in 1 proband, which is above the BP5 supporting threshold of 0.48.

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

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 Pathogenic (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely 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 no significant splice impact for this variant (max delta score = 0.07).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

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 ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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