Is BRCA2 p.Leu2865Ser (c.8594T>C) pathogenic?

BRCA2 p.Leu2865Ser (c.8594T>C) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-18). AlphaMissense: ambiguous (0.4365); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Leu2865Ser (c.8594T>C)?

BRCA2 p.Leu2865Ser (c.8594T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA2 p.Leu2865Ser (c.8594T>C) in the general population?

BRCA2 p.Leu2865Ser (c.8594T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Leu2865Ser (c.8594T>C)?

AlphaMissense predicts ambiguous (score 0.4365) — an in-silico prediction, not a clinical call.

BRCA2 p.Leu2865Ser

c.8594T>C · rs80359118 · VCV1503980

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4365 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4365	ambiguous · top 10% in BRCA2
REVEL	0.757	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 0.00024 · regional, not allelic
Overall
CADD	25.6	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.Leu2865Ser
Coding: c.8594T>C
MANE Select: NM_000059
dbSNP: rs80359118
Type: single nucleotide variant
Location: chr13:32371062 (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

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

Also linked: hereditary breast ovarian cancer syndrome

Similar variants

BRCA2 p.Leu2865Ile Uncertain significance ★★ same residue
BRCA2 p.Leu2865Val Conflicting classifications of pathogenicity ★ same residue
BRCA2 p.Leu2865= Likely benign ★ same residue
BRCA2 p.Leu2865Phe Likely benign ★ same residue
BRCA2 p.Leu2865fs Pathogenic ★★★ same residue
BRCA2 p.Leu2865Ter Pathogenic ★★★ 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-leu2865ser (accessed [today's date]).

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