Is BRCA1 p.Asn542fs (c.1623dup) pathogenic?

BRCA1 p.Asn542fs (c.1623dup) is classified Pathogenic in BRCA1 (ClinVar, Expert panel, 5 submitters; last evaluated 2016-10-18). Very rare (popmax 0.00133%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Asn542fs (c.1623dup)?

BRCA1 p.Asn542fs (c.1623dup) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Asn542fs (c.1623dup) in the general population?

BRCA1 p.Asn542fs (c.1623dup) is very rare (popmax 0.00133%, 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.

BRCA1 p.Asn542fs

c.1623dup · rs397508891 · VCV54312

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 10 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP 0.18, phastCons 0.002
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,936 alleles

Overall 0.000657% 1/152,220 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.Asn542fs
Coding: c.1623dup
MANE Select: NM_007294
dbSNP: rs397508891
Type: Duplication
Location: chr17:43093907 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 542: the 'disordered' region

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

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Asn542= Likely benign ★★ same residue
BRCA1 p.Asn542Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Asn542Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Asn542Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 c.4186-1787_4358-1668dup Pathogenic ★★★ same condition
BRCA1 c.5155dup Pathogenic ★★★ same condition
BRCA1 p.Ala1070delinsValLeuMetLysTrpAlaProValLeuMetLysTer Pathogenic ★★★ same condition
BRCA1 p.Ala1279fs 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-asn542fs (accessed [today's date]).

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