Is BRCA2 p.Val2818Phe (c.8452G>T) pathogenic?

BRCA2 p.Val2818Phe (c.8452G>T) is classified Uncertain significance in BRCA2 (ClinVar, Expert panel, 9 submitters; last evaluated 2026-07-15). AlphaMissense: ambiguous (0.3466); Very rare (popmax 0.00133%, afr); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Val2818Phe (c.8452G>T)?

BRCA2 p.Val2818Phe (c.8452G>T) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D1 (ClinVar).

How common is BRCA2 p.Val2818Phe (c.8452G>T) in the general population?

BRCA2 p.Val2818Phe (c.8452G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BRCA2 p.Val2818Phe (c.8452G>T)?

AlphaMissense predicts ambiguous (score 0.3466) — an in-silico prediction, not a clinical call.

BRCA2 p.Val2818Phe

c.8452G>T · rs80359094 · VCV481607

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.3466 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

BRCA2-related cancer predisposition

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Uncertain Significance for BRCA2-related cancer predisposition. Applied ACMG criteria (verbatim):

PM2_Supporting PS3 BP4

Curation rationale (ClinGen, verbatim)

The c.8452G>T variant in BRCA2 is a missense variant predicted to cause substitution of Val by Phe at amino acid 2818 (p.(Val2818Phe)). This variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.00, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. A SpliceAI score of 0.03 predicts no impact on splicing (score threshold ≤0.1) (BP4 met). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:39779857, 39779848) (PS3 met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP4, PM2_Supporting, PS3).

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

Computational evidence

Protein change
AlphaMissense	0.3466	ambiguous
REVEL	0.39	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 0.21, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,018 alleles

Overall 6.2e-05% 1/1,613,858 alleles · very rare exomes 1/1,461,572 · genomes 0/152,286 · joint denominator

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.Val2818Phe
Coding: c.8452G>T
MANE Select: NM_000059
dbSNP: rs80359094
Type: single nucleotide variant
Location: chr13:32370522 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2818: the 'interaction with sem1' region

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

Disease context

Also linked: hereditary breast ovarian cancer syndrome Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome

Similar variants

BRCA2 p.Val2818= Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Val2818Ala Uncertain significance ★ same residue
BRCA2 p.Val2818Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Val2818fs 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
BRCA2 c.316+5G>C 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-val2818phe (accessed [today's date]).

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