Is BRCA2 p.Ser2148Pro (c.6442T>C) pathogenic?

BRCA2 p.Ser2148Pro (c.6442T>C) is classified Likely benign in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0806); Very rare (popmax 0.00116%, sas); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Ser2148Pro (c.6442T>C)?

BRCA2 p.Ser2148Pro (c.6442T>C) is associated with breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Ser2148Pro (c.6442T>C) in the general population?

BRCA2 p.Ser2148Pro (c.6442T>C) is very rare (popmax 0.00116%, sas) (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.Ser2148Pro (c.6442T>C)?

AlphaMissense predicts likely benign (score 0.0806) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser2148Pro

c.6442T>C · VCV4856600

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00116%, sas)

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.0806	likely benign
REVEL	0.479	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.49	GERP -3.2
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	2.121	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

Grpmax group 0.00116% South Asian · 1/86,364 alleles

Overall 6.29e-05% 1/1,591,058 alleles · very rare exomes 1/1,438,760 · genomes 0/152,298 · 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.Ser2148Pro
Coding: c.6442T>C
MANE Select: NM_000059
Type: single nucleotide variant
Location: chr13:32340797 (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-ovarian cancer, familial, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ser2148= Likely benign ★★★ same residue
BRCA2 p.Ser2148Tyr Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser2148_Ile2149insTer Pathogenic ★★★ same residue
BRCA2 p.Ser2148fs Pathogenic ★★★ same residue
BRCA2 p.Ser2148Ala Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser2148Cys Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser2148Phe Conflicting classifications of pathogenicity ★ same residue
BRCA2 c.316+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-ser2148pro (accessed [today's date]).

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