Is BRCA2 p.Ser1069Phe (c.3206C>T) pathogenic?

BRCA2 p.Ser1069Phe (c.3206C>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1792); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA2 p.Ser1069Phe (c.3206C>T)?

BRCA2 p.Ser1069Phe (c.3206C>T) is associated with hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Ser1069Phe (c.3206C>T) in the general population?

BRCA2 p.Ser1069Phe (c.3206C>T) is absent from gnomAD v4.1 (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.Ser1069Phe (c.3206C>T)?

AlphaMissense predicts likely benign (score 0.1792) — an in-silico prediction, not a clinical call.

BRCA2 p.Ser1069Phe

c.3206C>T · rs80358563 · VCV51423

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1792 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,607,072)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.1792	likely benign
REVEL	0.147	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1.2, phastCons 0.34
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	19.61	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,607,072). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BRCA2
Protein: p.Ser1069Phe
Coding: c.3206C>T
MANE Select: NM_000059
dbSNP: rs80358563
Type: single nucleotide variant
Location: chr13:32337561 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1069: the 'interaction with rad51' region

Full BRCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: breast-ovarian cancer, familial, susceptibility to, 2 hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Ser1069Ala Uncertain significance ★ ⚠ same residue
BRCA2 p.Ser1069Pro Uncertain significance ★ ⚠ same residue
BRCA2 p.Ser1069= Likely benign ★ same residue
BRCA2 p.Ser1069Ter Pathogenic ★★★ same residue
BRCA2 p.Ser1069delinsLeuIleAlaValAsnTer Pathogenic ★★ same residue
BRCA2 p.Ser1069fs Pathogenic/Likely pathogenic ★★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same condition
BRCA2 c.316+2T>C 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-ser1069phe (accessed [today's date]).

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