Is BRCA2 p.Gly3076Glu (c.9227G>A) pathogenic?

BRCA2 p.Gly3076Glu (c.9227G>A) is classified Likely pathogenic in BRCA2 (ClinVar, Expert panel, 12 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.9881); Very rare (popmax 8.48e-05%, nfe); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Gly3076Glu (c.9227G>A)?

BRCA2 p.Gly3076Glu (c.9227G>A) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA2 p.Gly3076Glu (c.9227G>A) in the general population?

BRCA2 p.Gly3076Glu (c.9227G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about BRCA2 p.Gly3076Glu (c.9227G>A)?

AlphaMissense predicts likely pathogenic (score 0.9881) — an in-silico prediction, not a clinical call.

BRCA2 p.Gly3076Glu

c.9227G>A · rs80359187 · VCV52780

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.9881	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA2
REVEL	0.915	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,926 alleles

Overall 6.84e-05% 1/1,461,518 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Likely Pathogenic for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):

PP4_Strong PS3 PP3

Curation rationale (ClinGen, verbatim)

The c.9227G>A variant in BRCA2 is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at amino acid 3076 (p.(Gly3076Glu)). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Reported by four calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 32444794, 39779857, 39779848) (PS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.48, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 44.26 (based on Cosegregation LR=1.81; Family History LR=24.47), within the thresholds for strong evidence towards pathogenicity (LR >18.7 & ≤350) (PP4_Strong met; PMID: 31853058, Internal lab contributor). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PP3, PP4_Strong).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Variant & gene context

Gene: BRCA2
Protein: p.Gly3076Glu
Coding: c.9227G>A
MANE Select: NM_000059
dbSNP: rs80359187
Type: single nucleotide variant
Location: chr13:32380116 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3076: a UniProt-annotated variant site (in bc; also found in pancreatic cancer; decreased homology-directed repair activity)

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1 breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome

Similar variants

BRCA2 p.Gly3076Val Pathogenic ★★★ same residue
BRCA2 p.Gly3076= Likely benign ★★★ same residue
BRCA2 p.Gly3076Arg Likely pathogenic ★ same residue
BRCA2 p.Gly3076Ter Pathogenic ★ same residue
BRCA2 p.Gly3076fs Pathogenic ★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C Pathogenic ★★★ same condition
BRCA2 c.316+5G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/brca2-p-gly3076glu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown