Is BRCA2 p.Leu2688His (c.8063T>A) pathogenic?

BRCA2 p.Leu2688His (c.8063T>A) is classified Likely pathogenic in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.9405); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Leu2688His (c.8063T>A)?

BRCA2 p.Leu2688His (c.8063T>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA2 p.Leu2688His (c.8063T>A) in the general population?

BRCA2 p.Leu2688His (c.8063T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Leu2688His (c.8063T>A)?

AlphaMissense predicts likely pathogenic (score 0.9405) — an in-silico prediction, not a clinical call.

BRCA2 p.Leu2688His

c.8063T>A · VCV4819606

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9405 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9405	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA2
REVEL	0.919	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 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	26.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA2
Protein: p.Leu2688His
Coding: c.8063T>A
MANE Select: NM_000059
Type: single nucleotide variant
Location: chr13:32363265 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2688: the 'interaction with sem1' region

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

Disease context

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

Similar variants

BRCA2 p.Leu2688Pro Pathogenic/Likely pathogenic ★★ same residue
BRCA2 p.Leu2688Arg Uncertain significance ★★ ⚠ same residue
BRCA2 p.Leu2688= Likely benign ★★ same residue
BRCA2 p.Leu2688Val Uncertain significance ★ ⚠ same residue
BRCA2 p.Leu2688fs Pathogenic ★ same residue
BRCA2 p.Leu2688Ile Uncertain significance ★ ⚠ same residue
BRCA2 p.Leu2688Phe Uncertain significance ★ ⚠ same residue
BRCA2 c.316+1G>T 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-leu2688his (accessed [today's date]).

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