Is BRCA2 p.Pro89Leu (c.266C>T) pathogenic?

BRCA2 p.Pro89Leu (c.266C>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.1313); Ultra-rare (popmax 0.033%, mid); Associated with BRCA2-related disorder.

What condition is associated with BRCA2 p.Pro89Leu (c.266C>T)?

BRCA2 p.Pro89Leu (c.266C>T) is associated with BRCA2-related disorder, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Pro89Leu (c.266C>T) in the general population?

BRCA2 p.Pro89Leu (c.266C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about BRCA2 p.Pro89Leu (c.266C>T)?

AlphaMissense predicts likely benign (score 0.1313) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro89Leu

c.266C>T · rs748609599 · VCV409565

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1313 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

BRCA2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1313	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -1.7, phastCons 0.001
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	14.74	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00062% 10/1,613,776 alleles · ultra-rare exomes 10/1,461,508 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
East Asian	0.00446%	22,434
South Asian	0.00329%	30,359
European (non-Finnish)	0.000254%	393,244

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.Pro89Leu
Coding: c.266C>T
MANE Select: NM_000059
dbSNP: rs748609599
Type: single nucleotide variant
Location: chr13:32319275 (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

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

Similar variants

BRCA2 p.Pro89= Likely benign ★★★ same residue
BRCA2 p.Pro89Gln Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro89fs 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
BRCA2 c.475+1G>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-pro89leu (accessed [today's date]).

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