Is BRCA2 p.Asp2723His (c.8167G>C) pathogenic?

BRCA2 p.Asp2723His (c.8167G>C) is classified Pathogenic in BRCA2 (ClinVar, Expert panel, 38 submitters; last evaluated 2015-08-10). AlphaMissense: likely pathogenic (0.9871); Very rare (popmax 0.00178%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Asp2723His (c.8167G>C)?

BRCA2 p.Asp2723His (c.8167G>C) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, exocrine pancreatic carcinoma (ClinVar).

How common is BRCA2 p.Asp2723His (c.8167G>C) in the general population?

BRCA2 p.Asp2723His (c.8167G>C) is very rare (popmax 0.00178%, 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.

What do computational predictors say about BRCA2 p.Asp2723His (c.8167G>C)?

AlphaMissense predicts likely pathogenic (score 0.9871) — an in-silico prediction, not a clinical call.

BRCA2 p.Asp2723His

c.8167G>C · rs41293511 · VCV52515

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 38 submitters

AlphaMissense

likely pathogenic

0.9871 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.9871	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA2
REVEL	0.932	strongly pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	27.7	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 0.00178% European (non-Finnish) · 21/1,180,042 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00097%

Overall 0.0013% 21/1,614,046 alleles · very rare

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.Asp2723His
Coding: c.8167G>C
MANE Select: NM_000059
dbSNP: rs41293511
Type: single nucleotide variant
Location: chr13:32363369 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2723: a UniProt-annotated variant site (in bc; pathogenic; major splicing aberration identified with this mutant; reduced homology-directed repair activity); a UniProt-annotated variant site (in bc; pathogenic; disrupts interaction with sem1 promoting interaction with xpo1 and brca2 cytoplasmic localization; in heterozygous state promotes rad51 cytoplasmic localization; reduced homology-directed repair activity); the 'interaction with sem1' 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 exocrine pancreatic carcinoma breast cancer medulloblastoma prostate cancer Wilms tumor 1 breast-ovarian cancer, familial, susceptibility to, 1 Fanconi anemia complementation group D1 glioma susceptibility 3 pancreatic cancer, susceptibility to, 2 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.Asp2723Ala Pathogenic ★★★ same residue
BRCA2 p.Asp2723Gly Pathogenic ★★★ same residue
BRCA2 p.Asp2723Val Pathogenic/Likely pathogenic ★★ same residue
BRCA2 p.Asp2723= Likely benign ★★ same residue
BRCA2 p.Asp2723Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Asp2723Glu Conflicting classifications of pathogenicity ★ ⚠ 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-asp2723his (accessed [today's date]).

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