Is BRCA2 p.Met192Lys (c.575T>A) pathogenic?

BRCA2 p.Met192Lys (c.575T>A) is classified Uncertain significance in BRCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-16). AlphaMissense: likely pathogenic (0.8434); Absent from gnomAD v4.1.

How common is BRCA2 p.Met192Lys (c.575T>A) in the general population?

BRCA2 p.Met192Lys (c.575T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA2 p.Met192Lys (c.575T>A)?

AlphaMissense predicts likely pathogenic (score 0.8434) — an in-silico prediction, not a clinical call.

BRCA2 p.Met192Lys

c.575T>A · rs80358805 · VCV1331420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8434 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.8434	likely pathogenic · top 3% in BRCA2
REVEL	0.257	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	23.7	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.Met192Lys
Coding: c.575T>A
MANE Select: NM_000059
dbSNP: rs80358805
Type: single nucleotide variant
Location: chr13:32326557 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 192: a UniProt-annotated variant site (in one patient with pancreatic cancer)

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

Similar variants

BRCA2 p.Met192Arg Uncertain significance ★★ ⚠ same residue
BRCA2 p.Met192Val Uncertain significance ★★ same residue
BRCA2 p.Met192Ile Uncertain significance ★ ⚠ same residue
BRCA2 p.Met192Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA2 p.Met192fs Pathogenic ★★★ same residue
BRCA2 c.316+1G>T Pathogenic ★★★ same type
BRCA2 c.316+2T>C Pathogenic ★★★ same type
BRCA2 c.316+5G>A Pathogenic ★★★ same type

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-met192lys (accessed [today's date]).

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