Is BRCA1 p.Met1Ile (c.3G>C) pathogenic?

BRCA1 p.Met1Ile (c.3G>C) is classified Pathogenic in BRCA1 (ClinVar, Single submitter, 2 submitters; last evaluated 2015-10-02). Absent from gnomAD v4.1; Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Met1Ile (c.3G>C)?

BRCA1 p.Met1Ile (c.3G>C) is associated with breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Met1Ile (c.3G>C) in the general population?

BRCA1 p.Met1Ile (c.3G>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

BRCA1 p.Met1Ile

c.3G>C · rs80357475 · VCV267523

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.696	pathogenic-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	phastCons 1
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Met1Ile
Coding: c.3G>C
MANE Select: NM_007294
dbSNP: rs80357475
Type: single nucleotide variant
Location: chr17:43124094 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1: a modified residue (n-acetylmethionine)

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

Disease context

breast-ovarian cancer, familial, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Met1Arg Pathogenic ★★ same residue
BRCA1 p.Met1Thr Pathogenic ★★ same residue
BRCA1 p.Met1Val Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Met1Lys Pathogenic ★ 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
BRCA1 c.212+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/brca1-p-met1ile (accessed [today's date]).

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