Is BRCA1 p.Met1663Lys (c.4988T>A) pathogenic?

BRCA1 p.Met1663Lys (c.4988T>A) is classified Uncertain significance in BRCA1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-07-30). AlphaMissense: likely benign (0.0927); Very rare (popmax 0.000765%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Met1663Lys (c.4988T>A)?

BRCA1 p.Met1663Lys (c.4988T>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Met1663Lys (c.4988T>A) in the general population?

BRCA1 p.Met1663Lys (c.4988T>A) is very rare (popmax 0.000765%, nfe) (gnomAD).

What do computational predictors say about BRCA1 p.Met1663Lys (c.4988T>A)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

BRCA1 p.Met1663Lys

c.4988T>A · rs80357205 · VCV55349

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000765%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.629	indeterminate
SaProt	LLR -2.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.37	acceptor loss, 1 bp away · raw score · deltas
Pangolin	Δ0.31	loss · gain 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP -0.66, phastCons 0.35
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	15.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000765% European (non-Finnish) · 9/1,175,866 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000823% 12/1,457,250 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,789
European (non-Finnish)grpmax	0.000765%	130,652

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Met1663Lys
Coding: c.4988T>A
MANE Select: NM_007294
dbSNP: rs80357205
Type: single nucleotide variant
Location: chr17:43067694 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1663: the brct 1 domain; a UniProt-annotated variant site (in fancs); an α-helix

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 breast-ovarian cancer, familial, susceptibility to, 1

Similar variants

BRCA1 p.Met1663Thr Uncertain significance ★★ ⚠ same residue
BRCA1 p.Met1663Arg Likely pathogenic ★ ⚠ same residue
BRCA1 p.Met1663Leu Uncertain significance ★ ⚠ same residue
BRCA1 p.Met1663Ile Uncertain significance ⚠ same residue
BRCA1 p.Met1663fs 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

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-met1663lys (accessed [today's date]).

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