Is BRCA2 p.Pro3300Ser (c.9898C>T) pathogenic?

BRCA2 p.Pro3300Ser (c.9898C>T) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.4691); Very rare (popmax 0.00446%, eas); Associated with Breast and/or ovarian cancer.

What condition is associated with BRCA2 p.Pro3300Ser (c.9898C>T)?

BRCA2 p.Pro3300Ser (c.9898C>T) is associated with Breast and/or ovarian cancer, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Pro3300Ser (c.9898C>T) in the general population?

BRCA2 p.Pro3300Ser (c.9898C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BRCA2 p.Pro3300Ser (c.9898C>T)?

AlphaMissense predicts ambiguous (score 0.4691) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro3300Ser

c.9898C>T · rs770868371 · VCV246104

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.4691	ambiguous · top 9% in BRCA2
REVEL	0.235	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	25.3	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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,878 alleles · very rare

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.Pro3300Ser
Coding: c.9898C>T
MANE Select: NM_000059
dbSNP: rs770868371
Type: single nucleotide variant
Location: chr13:32398411 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3300: a UniProt-annotated variant site (in one patient with esophageal carcinoma); the 'tr2 region' region; an α-helix

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

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BRCA2 p.Pro3300Thr Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro3300= Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Pro3300Gln Uncertain significance ★ ⚠ same residue
BRCA2 p.Pro3300Leu Uncertain significance ★ ⚠ 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-pro3300ser (accessed [today's date]).

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