Is BRCA2 p.Pro2283Ala (c.6847C>G) pathogenic?

BRCA2 p.Pro2283Ala (c.6847C>G) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-11-22). AlphaMissense: likely benign (0.1031); Very rare (popmax 0.000182%, nfe); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Pro2283Ala (c.6847C>G)?

BRCA2 p.Pro2283Ala (c.6847C>G) is associated with hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Pro2283Ala (c.6847C>G) in the general population?

BRCA2 p.Pro2283Ala (c.6847C>G) is very rare (popmax 0.000182%, nfe) (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.

What do computational predictors say about BRCA2 p.Pro2283Ala (c.6847C>G)?

AlphaMissense predicts likely benign (score 0.1031) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro2283Ala

c.6847C>G · rs80358909 · VCV52213

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000182%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.1031	likely benign
REVEL	0.723	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	20.7	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 0.000182% European (non-Finnish) · 2/1,097,326 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000219% 3/1,367,144 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00169%	59,294
European (non-Finnish)grpmax	0.000182%	548,664

Remaining individuals 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.Pro2283Ala
Coding: c.6847C>G
MANE Select: NM_000059
dbSNP: rs80358909
Type: single nucleotide variant
Location: chr13:32344563 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2283: the 'interaction with hsf2bp' region

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 hereditary breast carcinoma BRCA2-related cancer predisposition

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Pro2283His Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro2283Leu Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro2283Ser Uncertain significance ★ same residue
BRCA2 p.Pro2283Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Pro2283= Likely benign ★ 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-pro2283ala (accessed [today's date]).

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