Is BRCA1 p.Pro684Ser (c.2050C>T) pathogenic?

BRCA1 p.Pro684Ser (c.2050C>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2025-12-13). AlphaMissense: likely benign (0.1094); Very rare (popmax 0.00195%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with BRCA1 p.Pro684Ser (c.2050C>T)?

BRCA1 p.Pro684Ser (c.2050C>T) is associated with hereditary breast carcinoma, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Pro684Ser (c.2050C>T) in the general population?

BRCA1 p.Pro684Ser (c.2050C>T) is very rare (popmax 0.00195%, nfe) (gnomAD).

How is Hereditary breast cancer inherited?

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

What do computational predictors say about BRCA1 p.Pro684Ser (c.2050C>T)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

BRCA1 p.Pro684Ser

c.2050C>T · rs397508934 · VCV54447

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -4.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -2.8, phastCons 0.21
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	9.829	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

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,994 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,304
African / African-American	0.00133%	74,910

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.Pro684Ser
Coding: c.2050C>T
MANE Select: NM_007294
dbSNP: rs397508934
Type: single nucleotide variant
Location: chr17:43093481 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 684: the 'disordered' region

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

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1 pancreatic cancer, susceptibility to, 4 hereditary neoplastic syndrome Fanconi anemia, complementation group S BRCA1-related cancer predisposition

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BRCA1 p.Pro684Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Pro684Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Pro684= Likely benign ★ 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-pro684ser (accessed [today's date]).

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