Is BRCA1 p.Glu121= (c.363A>G) pathogenic?

BRCA1 p.Glu121= (c.363A>G) is classified Likely benign in BRCA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-07). Very rare (popmax 0.00017%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Glu121= (c.363A>G)?

BRCA1 p.Glu121= (c.363A>G) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Glu121= (c.363A>G) in the general population?

BRCA1 p.Glu121= (c.363A>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

BRCA1 p.Glu121=

c.363A>G · rs1060504552 · VCV415545

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.053	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.41	GERP -0.42, phastCons 0.31
Overall
CADD	4.256	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,640 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,724 alleles · very rare exomes 2/1,461,402 · genomes 0/152,322 · 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.Glu121=
Coding: c.363A>G
MANE Select: NM_007294
dbSNP: rs1060504552
Type: single nucleotide variant
Location: chr17:43104200 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB

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.Glu121Gly Uncertain significance ★ ⚠ same residue
BRCA1 p.Glu121Lys Uncertain significance ★ ⚠ same residue
BRCA1 p.Glu121fs 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
BRCA1 c.212+3A>G 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-glu121 (accessed [today's date]).

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