Is BRCA2 p.Ser2998Ala (c.8992T>G) pathogenic?

BRCA2 p.Ser2998Ala (c.8992T>G) is classified Uncertain significance in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely benign (0.0759); Ultra-rare (popmax 0.0165%, mid); Associated with Breast and/or ovarian cancer.

What condition is associated with BRCA2 p.Ser2998Ala (c.8992T>G)?

BRCA2 p.Ser2998Ala (c.8992T>G) is associated with Breast and/or ovarian cancer (ClinVar).

How common is BRCA2 p.Ser2998Ala (c.8992T>G) in the general population?

BRCA2 p.Ser2998Ala (c.8992T>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BRCA2 p.Ser2998Ala (c.8992T>G)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser2998Ala

c.8992T>G · rs1442009294 · VCV2691152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.274	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.45	acceptor loss, 13 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 2.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	23.0	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 0.0165% Middle Eastern · 1/6,054 alleles

Overall 6.2e-05% 1/1,612,784 alleles · ultra-rare exomes 1/1,460,470 · genomes 0/152,314 · 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.Ser2998Ala
Coding: c.8992T>G
MANE Select: NM_000059
dbSNP: rs1442009294
Type: single nucleotide variant
Location: chr13:32379788 (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

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

Similar variants

BRCA2 p.Ser2998Phe Uncertain significance ★★ same residue
BRCA2 p.Ser2998Tyr Uncertain significance ★★ same residue
BRCA2 p.Ser2998= Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser2998Thr Likely benign ★ same residue
BRCA2 p.Ser2998fs Pathogenic ★★★ same residue
BRCA2 p.Asp2723Val Pathogenic/Likely pathogenic ★★ same condition
BRCA2 p.Leu2653Pro Pathogenic/Likely pathogenic ★★ same condition
BRCA2 p.Pro3300Ser Uncertain significance ★★ 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-ser2998ala (accessed [today's date]).

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