Is BRCA2 p.Phe2293Leu (c.6877T>C) pathogenic?

BRCA2 p.Phe2293Leu (c.6877T>C) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.9589); Ultra-rare (popmax 0.0302%, amr); Associated with Wilms tumor 1.

What condition is associated with BRCA2 p.Phe2293Leu (c.6877T>C)?

BRCA2 p.Phe2293Leu (c.6877T>C) is associated with Wilms tumor 1, hereditary breast ovarian cancer syndrome, medulloblastoma (ClinVar).

How common is BRCA2 p.Phe2293Leu (c.6877T>C) in the general population?

BRCA2 p.Phe2293Leu (c.6877T>C) is ultra-rare (popmax 0.0302%, amr) (gnomAD).

What do computational predictors say about BRCA2 p.Phe2293Leu (c.6877T>C)?

AlphaMissense predicts likely pathogenic (score 0.9589) — an in-silico prediction, not a clinical call.

BRCA2 p.Phe2293Leu

c.6877T>C · rs80358912 · VCV52216

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0302%, amr)

Conditions

Wilms tumor 1

Computational evidence

Protein change
AlphaMissense	0.9589	likely pathogenic · top 1% in BRCA2
REVEL	0.604	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	24.2	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 0.0302% Admixed American · 18/59,618 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0161%

Overall 0.00133% 19/1,425,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0302%	3,312
Remaining individualsnot grpmax-eligible	0.00163%	61,236

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.Phe2293Leu
Coding: c.6877T>C
MANE Select: NM_000059
dbSNP: rs80358912
Type: single nucleotide variant
Location: chr13:32344593 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2293: a UniProt-annotated variant site (in bc; uncertain significance and); the 'interaction with hsf2bp' region

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

Disease context

Wilms tumor 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome medulloblastoma prostate cancer Fanconi anemia complementation group D1 breast-ovarian cancer, familial, susceptibility to, 2 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma BRCA2-related cancer predisposition prostate cancer, hereditary

Similar variants

BRCA2 p.Phe2293= Likely benign ★ same residue
BRCA2 p.Phe2293fs Pathogenic/Likely 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
BRCA2 c.475+1G>T 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-phe2293leu (accessed [today's date]).

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