Is BRCA2 p.Asp1709Tyr (c.5125G>T) pathogenic?

BRCA2 p.Asp1709Tyr (c.5125G>T) is classified Conflicting classifications of pathogenicity in BRCA2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-05-12). AlphaMissense: likely benign (0.1186); Very rare (popmax 0.00562%, amr); Associated with Fanconi anemia complementation group D1.

What condition is associated with BRCA2 p.Asp1709Tyr (c.5125G>T)?

BRCA2 p.Asp1709Tyr (c.5125G>T) is associated with Fanconi anemia complementation group D1, hereditary breast ovarian cancer syndrome, medulloblastoma (ClinVar).

How common is BRCA2 p.Asp1709Tyr (c.5125G>T) in the general population?

BRCA2 p.Asp1709Tyr (c.5125G>T) is very rare (popmax 0.00562%, amr) (gnomAD).

What do computational predictors say about BRCA2 p.Asp1709Tyr (c.5125G>T)?

AlphaMissense predicts likely benign (score 0.1186) — an in-silico prediction, not a clinical call.

BRCA2 p.Asp1709Tyr

Q: How is Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.5125G>T · rs398122792 · VCV91833

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.1186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00562%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Fanconi anemia complementation group D1

Computational evidence

Protein change
AlphaMissense	0.1186	likely benign
REVEL	0.166	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 -0.7	GERP -4.8
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	4.681	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

Grpmax group 0.00562% Admixed American · 3/53,394 alleles

Filtering AF 0.00149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000813%

Overall 0.00028% 4/1,431,026 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00562%	17,798
Remaining individualsnot grpmax-eligible	0.00164%	61,072

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.Asp1709Tyr
Coding: c.5125G>T
MANE Select: NM_000059
dbSNP: rs398122792
Type: single nucleotide variant
Location: chr13:32339480 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 1709: the 'interaction with rad51' region; the 'interaction with polh' region

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

Disease context

Fanconi anemia complementation group D1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome medulloblastoma Wilms tumor 1 breast-ovarian cancer, familial, susceptibility to, 2 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 hereditary neoplastic syndrome hereditary breast carcinoma prostate cancer, hereditary

For Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations (Orphanet):

Inheritance: Autosomal recessive

Similar variants

BRCA2 p.Asp1709= Likely benign ★★ same residue
BRCA2 p.Asp1709Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp1709Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp1709Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp1709His Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp1709Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp1709_Tyr1710insTer Pathogenic ★★★ same residue
BRCA2 p.Asp1709fs Pathogenic ★★★ same residue

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-asp1709tyr (accessed [today's date]).

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