Is BRCA2 p.Leu198Ser (c.593T>C) pathogenic?

BRCA2 p.Leu198Ser (c.593T>C) is classified Uncertain significance in BRCA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-20). AlphaMissense: likely pathogenic (0.9492); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA2 p.Leu198Ser (c.593T>C)?

BRCA2 p.Leu198Ser (c.593T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 2 (ClinVar).

How common is BRCA2 p.Leu198Ser (c.593T>C) in the general population?

BRCA2 p.Leu198Ser (c.593T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Leu198Ser (c.593T>C)?

AlphaMissense predicts likely pathogenic (score 0.9492) — an in-silico prediction, not a clinical call.

BRCA2 p.Leu198Ser

c.593T>C · rs778528034 · VCV927407

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9492 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9492	likely pathogenic · top 1% in BRCA2
REVEL	0.171	moderately 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 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 47 kb · p 0.059 · regional, not allelic
Overall
CADD	23.6	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.Leu198Ser
Coding: c.593T>C
MANE Select: NM_000059
dbSNP: rs778528034
Type: single nucleotide variant
Location: chr13:32326575 (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 breast-ovarian cancer, familial, susceptibility to, 2

Similar variants

BRCA2 p.Leu198Val Uncertain significance ★ ⚠ same residue
BRCA2 p.Leu198= Likely benign ★ same residue
BRCA2 p.Leu198_Ala199delinsTer Pathogenic ★★★ 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
BRCA2 c.475+1G>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-leu198ser (accessed [today's date]).

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