Is ATM p.Glu2139fs (c.6415_6416del) pathogenic?

ATM p.Glu2139fs (c.64156416del) is classified Pathogenic in ATM (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-13). Very rare (popmax 0.000425%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with ATM p.Glu2139fs (c.6415_6416del)?

ATM p.Glu2139fs (c.6415_6416del) is associated with hereditary breast carcinoma, ataxia telangiectasia, hereditary neoplastic syndrome (ClinVar).

How common is ATM p.Glu2139fs (c.6415_6416del) in the general population?

ATM p.Glu2139fs (c.6415_6416del) is very rare (popmax 0.000425%, 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.Glu2139fs

c.6415_6416del · rs863225466 · VCV218278

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000425%, 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 44 of 63
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.005	GERP -3.7, phastCons 0.81

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000425% European (non-Finnish) · 5/1,177,614 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,611,278 alleles · very rare exomes 5/1,459,014 · genomes 0/152,264 · joint denominator

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.Glu2139fs
Coding: c.6415_6416del
MANE Select: NM_000051
dbSNP: rs863225466
Type: Microsatellite
Location: chr11:108320018 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 2139: a UniProt-annotated variant site (in at; uncertain significance; reduces protein abundance); a UniProt-annotated variant site (in t-prolymphocytic leukemia; somatic mutation); a UniProt-annotated variant site (in at); the fat domain; a UniProt-annotated variant site (in at; uncertain significance); a UniProt-annotated variant site (in at; uncertain significance; increases protein abundance)

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.Glu2139Ter Pathogenic/Likely pathogenic ★★ same residue
ATM p.Glu2139= Likely benign ★ same residue
ATM p.Glu522fs Pathogenic ★★★ same condition
ATM p.Leu2307fs Pathogenic ★★★ same condition
ATM p.Leu762fs Pathogenic ★★★ same condition
ATM p.Phe2799fs Pathogenic ★★★ same condition
ATM p.Ser2860del Pathogenic ★★★ same condition
ATM c.75_78del Pathogenic/Likely 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-glu2139fs (accessed [today's date]).

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