Is ATM p.Lys331fs (c.992del) pathogenic?

ATM p.Lys331fs (c.992del) is classified Pathogenic in ATM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-01-11). Very rare (popmax 8.48e-05%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with ATM p.Lys331fs (c.992del)?

ATM p.Lys331fs (c.992del) is associated with hereditary breast carcinoma, ataxia telangiectasia, hereditary neoplastic syndrome (ClinVar).

How common is ATM p.Lys331fs (c.992del) in the general population?

ATM p.Lys331fs (c.992del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Hereditary breast cancer inherited?

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

ATM p.Lys331fs

c.992del · rs1060501684 · VCV407696

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hereditary breast carcinoma

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 8 of 63
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,798 alleles

Overall 0.000124% 2/1,613,794 alleles · very rare exomes 2/1,461,470 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)grpmax	8.48e-05%	1,179,798

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: ATM
Protein: p.Lys331fs
Coding: c.992del
MANE Select: NM_000051
dbSNP: rs1060501684
Type: Deletion
Location: chr11:108247052 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 331: a UniProt-annotated variant site (in at)

Full ATM 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: ataxia telangiectasia hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

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

Similar variants

ATM p.Lys331Asn Uncertain significance ★★ ⚠ same residue
ATM p.Lys331Glu Uncertain significance ★★ same residue
ATM p.Lys331= Benign/Likely benign ★★ same residue
ATM p.Lys331Arg Uncertain significance ★ ⚠ same residue
ATM p.Lys331Met Uncertain significance ★ same residue
ATM c.2639-22_2639-20del Pathogenic ★★★ same condition
ATM p.Ala2045_Leu2046insTer Pathogenic ★★★ same condition
ATM p.Asn1719fs 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/atm-p-lys331fs (accessed [today's date]).

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