Is BRCA2 p.Tyr2726Cys (c.8177A>G) pathogenic?

BRCA2 p.Tyr2726Cys (c.8177A>G) is classified Pathogenic/Likely pathogenic in BRCA2 (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-26). AlphaMissense: likely pathogenic (0.8863); Very rare (popmax 0.0011%, sas); Associated with BRCA2-related cancer predisposition.

What condition is associated with BRCA2 p.Tyr2726Cys (c.8177A>G)?

BRCA2 p.Tyr2726Cys (c.8177A>G) is associated with BRCA2-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Tyr2726Cys (c.8177A>G) in the general population?

BRCA2 p.Tyr2726Cys (c.8177A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRCA2 p.Tyr2726Cys (c.8177A>G)?

AlphaMissense predicts likely pathogenic (score 0.8863) — an in-silico prediction, not a clinical call.

BRCA2 p.Tyr2726Cys

c.8177A>G · rs80359064 · VCV52520

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

AlphaMissense

likely pathogenic

0.8863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

BRCA2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.8863	likely pathogenic ✓ concordant with ClinVar · top 2% in BRCA2
REVEL	0.928	moderately 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 11	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	26.1	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 0.0011% South Asian · 1/91,092 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00031% 5/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,022
South Asiangrpmax	0.0011%	91,092
European (non-Finnish)	0.000169%	590,016

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Tyr2726Cys
Coding: c.8177A>G
MANE Select: NM_000059
dbSNP: rs80359064
Type: single nucleotide variant
Location: chr13:32363379 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2726: the 'interaction with sem1' region

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

Disease context

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

Similar variants

BRCA2 p.Tyr2726Ter Pathogenic ★★★ same residue
BRCA2 p.Tyr2726= Benign/Likely benign ★★ same residue
BRCA2 p.Tyr2726Asn Likely pathogenic ★ same residue
BRCA2 p.Tyr2726Phe 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
BRCA2 c.316+5G>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-tyr2726cys (accessed [today's date]).

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