Is BRCA2 p.Pro168Thr (c.502C>A) pathogenic?

BRCA2 p.Pro168Thr (c.502C>A) is classified Benign in BRCA2 (ClinVar, Expert panel, 12 submitters; last evaluated 2015-08-10). AlphaMissense: likely pathogenic (0.6613); Ultra-rare (popmax 0.045%, amr); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

What condition is associated with BRCA2 p.Pro168Thr (c.502C>A)?

BRCA2 p.Pro168Thr (c.502C>A) is associated with breast-ovarian cancer, familial, susceptibility to, 2, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Pro168Thr (c.502C>A) in the general population?

BRCA2 p.Pro168Thr (c.502C>A) is ultra-rare (popmax 0.045%, amr) (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.Pro168Thr (c.502C>A)?

AlphaMissense predicts likely pathogenic (score 0.6613) — an in-silico prediction, not a clinical call.

BRCA2 p.Pro168Thr

c.502C>A · rs80358726 · VCV51757

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.6613 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

breast-ovarian cancer, familial, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.6613	likely pathogenic · top 6% in BRCA2
REVEL	0.226	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	23.1	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 0.045% Admixed American · 27/59,988 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00669% 108/1,613,150 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.045%	2,222
Remaining individualsnot grpmax-eligible	0.00801%	12,488
European (non-Finnish)	0.00636%	15,725
African / African-American	0.00134%	74,890

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.Pro168Thr
Coding: c.502C>A
MANE Select: NM_000059
dbSNP: rs80358726
Type: single nucleotide variant
Location: chr13:32326268 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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 hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA2 p.Pro168Ala Uncertain significance ★★ same residue
BRCA2 p.Pro168Arg Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro168Gln Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro168Ser Uncertain significance ★★ ⚠ same residue
BRCA2 p.Pro168Leu Uncertain significance ★ ⚠ 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-pro168thr (accessed [today's date]).

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