Is BRCA1 p.Ile68= (c.204A>T) pathogenic?

BRCA1 p.Ile68= (c.204A>T) is classified Likely benign in BRCA1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-18). Very rare (popmax 6.28e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Ile68= (c.204A>T)?

BRCA1 p.Ile68= (c.204A>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Ile68= (c.204A>T) in the general population?

BRCA1 p.Ile68= (c.204A>T) is very rare (popmax 6.28e-05%) (gnomAD).

BRCA1 p.Ile68=

c.204A>T · rs1555597192 · VCV485377

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 6.28e-05%)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP -1.3, phastCons 1
Overall
CADD	9.228	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.28e-05%

Overall 6.28e-05% 1/1,592,154 alleles · very rare exomes 1/1,439,812 · genomes 0/152,342 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BRCA1
Protein: p.Ile68=
Coding: c.204A>T
MANE Select: NM_007294
dbSNP: rs1555597192
Type: single nucleotide variant
Location: chr17:43106464 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 68: a β-strand

Full BRCA1 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

BRCA1 p.Ile68Lys Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ile68Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ile68Met Uncertain significance ★ ⚠ same residue
BRCA1 p.Ile68Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ile68Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ile68fs Pathogenic ★★★ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>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-ile68 (accessed [today's date]).

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