Is BRCA2 p.Ser1538= (c.4614T>C) pathogenic?

BRCA2 p.Ser1538= (c.4614T>C) is classified Likely benign in BRCA2 (ClinVar, Expert panel, 26 submitters; last evaluated 2017-06-29). Ultra-rare (popmax 0.022%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Ser1538= (c.4614T>C)?

BRCA2 p.Ser1538= (c.4614T>C) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA2 p.Ser1538= (c.4614T>C) in the general population?

BRCA2 p.Ser1538= (c.4614T>C) is ultra-rare (popmax 0.022%, nfe) (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.Ser1538=

c.4614T>C · rs45520945 · VCV51683

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 26 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, nfe)

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 1.4	GERP -1.4, phastCons 1
Overall
CADD	7.233	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.022% European (non-Finnish) · 260/1,179,880 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.0166% 268/1,613,780 alleles · ultra-rare exomes 253/1,461,512 · genomes 15/152,268 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.022%	4,538
Remaining individualsnot grpmax-eligible	0.008%	12,499
African / African-American	0.00267%	37,493
Finnishnot grpmax-eligible	0.00156%	64,010

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.Ser1538=
Coding: c.4614T>C
MANE Select: NM_000059
dbSNP: rs45520945
Type: single nucleotide variant
Location: chr13:32338969 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1538: the 'interaction with rad51' region; the 'interaction with polh' region; the 'required for stimulation of polh dna polymerization activity' region; an α-helix

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 hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ser1538Cys Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser1538Phe Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser1538Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Ser1538Thr Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Ser1538Tyr 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

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-ser1538 (accessed [today's date]).

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