Is BRCA2 p.Glu2918= (c.8754G>A) pathogenic?

BRCA2 p.Glu2918= (c.8754G>A) is classified Pathogenic/Likely pathogenic in BRCA2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-02-24). Very rare (popmax 0.00167%, amr); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Glu2918= (c.8754G>A)?

BRCA2 p.Glu2918= (c.8754G>A) is associated with hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Glu2918= (c.8754G>A) in the general population?

BRCA2 p.Glu2918= (c.8754G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

BRCA2 p.Glu2918=

c.8754G>A · rs80359803 · VCV52671

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.83	loss · gain 0.58 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.5	GERP 2.1, phastCons 1
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,996 alleles

Overall 0.000137% 2/1,461,736 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
Admixed Americangrpmax	0.00167%	59,996

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.

Variant & gene context

Gene: BRCA2
Protein: p.Glu2918=
Coding: c.8754G>A
MANE Select: NM_000059
dbSNP: rs80359803
Type: single nucleotide variant
Location: chr13:32376791 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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

Disease context

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Glu2918Gln Uncertain significance ★★ same residue
BRCA2 p.Glu2918Asp Likely pathogenic ★ ⚠ same residue
BRCA2 p.Glu2918Ter Pathogenic ★ same residue
BRCA2 p.Glu2918Val Uncertain significance ★ same residue
BRCA2 p.Glu2918fs 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-glu2918 (accessed [today's date]).

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