Is BRCA2 p.Ser1528= (c.4584C>T) pathogenic?

BRCA2 p.Ser1528= (c.4584C>T) is classified Likely benign in BRCA2 (ClinVar, Expert panel, 30 submitters; last evaluated 2017-06-29). Ultra-rare (popmax 0.0934%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Ser1528= (c.4584C>T)?

BRCA2 p.Ser1528= (c.4584C>T) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Ser1528= (c.4584C>T) in the general population?

BRCA2 p.Ser1528= (c.4584C>T) is ultra-rare (popmax 0.0934%, afr) (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.

BRCA2 p.Ser1528=

c.4584C>T · rs80359788 · VCV51677

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 30 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0934%, afr)

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.89	GERP 0.058, phastCons 1
Overall
CADD	9.021	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0934% African / African-American · 70/74,938 alleles

Filtering AF 0.0757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0693%

Overall 0.0131% 212/1,613,660 alleles · ultra-rare exomes 172/1,461,560 · genomes 40/152,100 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0934%	1,071
Admixed American	0.0584%	1,713
Middle Eastern	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.032%	3,125
European (non-Finnish)	0.0067%	14,935
South Asian	0.00549%	18,204
East Asian	0.00223%	44,876

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.Ser1528=
Coding: c.4584C>T
MANE Select: NM_000059
dbSNP: rs80359788
Type: single nucleotide variant
Location: chr13:32338939 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1528: the 'interaction with rad51' region; the 'interaction with polh' region; the 'required for stimulation of polh dna polymerization activity' region

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

Also linked: hereditary breast ovarian cancer syndrome breast cancer Fanconi anemia complementation group D1 hereditary neoplastic syndrome hereditary breast carcinoma

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ser1528Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ser1528Asn Uncertain significance ★ same residue
BRCA2 p.Ser1528Gly Conflicting classifications of pathogenicity ★ 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
BRCA2 c.475+1G>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-ser1528 (accessed [today's date]).

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