Is BRCA2 p.Ser3250Leu (c.9749C>T) pathogenic?

BRCA2 p.Ser3250Leu (c.9749C>T) is classified Likely benign in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-09). AlphaMissense: likely benign (0.0786); Absent from gnomAD v4.1; Associated with hereditary breast carcinoma.

What condition is associated with BRCA2 p.Ser3250Leu (c.9749C>T)?

BRCA2 p.Ser3250Leu (c.9749C>T) is associated with hereditary breast carcinoma (ClinVar).

How common is BRCA2 p.Ser3250Leu (c.9749C>T) in the general population?

BRCA2 p.Ser3250Leu (c.9749C>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA2 p.Ser3250Leu (c.9749C>T)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser3250Leu

c.9749C>T · rs2137663473 · VCV1708988

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.181	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 2.1	GERP -0.43, phastCons 0.008
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	17.54	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA2
Protein: p.Ser3250Leu
Coding: c.9749C>T
MANE Select: NM_000059
dbSNP: rs2137663473
Type: single nucleotide variant
Location: chr13:32398262 (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

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ser3250Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ser3250fs Pathogenic ★★★ same residue
BRCA2 p.Ser3250= Likely benign ★★ same residue
BRCA2 p.Ser3250Ter Pathogenic ★ same residue
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>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-ser3250leu (accessed [today's date]).

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