Is BRCA1 p.Met1775Arg (c.5324T>G) pathogenic?

BRCA1 p.Met1775Arg (c.5324T>G) is classified Pathogenic in BRCA1 (ClinVar, Expert panel, 28 submitters; last evaluated 2015-08-10). AlphaMissense: likely pathogenic (0.893); Very rare (popmax 0.00667%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Met1775Arg (c.5324T>G)?

BRCA1 p.Met1775Arg (c.5324T>G) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Met1775Arg (c.5324T>G) in the general population?

BRCA1 p.Met1775Arg (c.5324T>G) is very rare (popmax 0.00667%, afr) (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.

What do computational predictors say about BRCA1 p.Met1775Arg (c.5324T>G)?

AlphaMissense predicts likely pathogenic (score 0.893) — an in-silico prediction, not a clinical call.

BRCA1 p.Met1775Arg

c.5324T>G · rs41293463 · VCV17694

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 28 submitters

AlphaMissense

likely pathogenic

0.893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.893	likely pathogenic ✓ concordant with ClinVar · top 3% in BRCA1
REVEL	0.728	pathogenic-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	23.5	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 0.00667% African / African-American · 5/74,910 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,613,936 alleles · very rare

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.Met1775Arg
Coding: c.5324T>G
MANE Select: NM_007294
dbSNP: rs41293463
Type: single nucleotide variant
Location: chr17:43051071 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1775: a UniProt-annotated variant site (in fancs); the brct 2 domain; a UniProt-annotated variant site (in bc; pathogenic; strongly reduced transcription transactivation; abolishes interaction with brip1 and rbbp8); a UniProt-annotated variant site (in bc; pathogenic; alters protein stability and abolishes acaca and brip1 binding); a β-strand

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

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome BRCA1-related cancer predisposition

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Met1775Lys Pathogenic ★★★ ⚠ same residue
BRCA1 p.Met1775Val Likely pathogenic ★ ⚠ same residue
BRCA1 p.Met1775Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Met1775fs Pathogenic ★★★ same residue
BRCA1 p.Met1775Ile 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-met1775arg (accessed [today's date]).

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