Is BRCA1 p.Met1689Lys (c.5066T>A) pathogenic?

BRCA1 p.Met1689Lys (c.5066T>A) is classified Likely pathogenic in BRCA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-27). AlphaMissense: likely pathogenic (0.9317); Absent from gnomAD v4.1; Associated with Inherited breast cancer and ovarian cancer.

What condition is associated with BRCA1 p.Met1689Lys (c.5066T>A)?

BRCA1 p.Met1689Lys (c.5066T>A) is associated with Inherited breast cancer and ovarian cancer, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Met1689Lys (c.5066T>A) in the general population?

BRCA1 p.Met1689Lys (c.5066T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Met1689Lys (c.5066T>A)?

AlphaMissense predicts likely pathogenic (score 0.9317) — an in-silico prediction, not a clinical call.

BRCA1 p.Met1689Lys

c.5066T>A · rs80357061 · VCV864899

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9317 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inherited breast cancer and ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.9317	likely pathogenic ✓ concordant with ClinVar · top 2% in BRCA1
REVEL	0.756	pathogenic-leaning
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · 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: BRCA1
Protein: p.Met1689Lys
Coding: c.5066T>A
MANE Select: NM_007294
dbSNP: rs80357061
Type: single nucleotide variant
Location: chr17:43067616 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1689: the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; uncertain significance); a β-strand

Full BRCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inherited breast cancer and ovarian cancer

Also linked: hereditary neoplastic syndrome

Similar variants

BRCA1 p.Met1689Arg Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Met1689Val Uncertain significance ★★ ⚠ same residue
BRCA1 p.Met1689Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Met1689Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Met1689Leu Uncertain significance ★★ ⚠ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T Pathogenic ★★★ same condition
BRCA1 c.212+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/brca1-p-met1689lys (accessed [today's date]).

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