Is ATM p.Phe680= (c.2040C>T) pathogenic?

ATM p.Phe680= (c.2040C>T) is classified Benign/Likely benign in ATM (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-06). Very rare (popmax 0.00517%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with ATM p.Phe680= (c.2040C>T)?

ATM p.Phe680= (c.2040C>T) is associated with hereditary neoplastic syndrome, ataxia telangiectasia, hereditary breast carcinoma (ClinVar).

How common is ATM p.Phe680= (c.2040C>T) in the general population?

ATM p.Phe680= (c.2040C>T) is very rare (popmax 0.00517%, nfe) (gnomAD).

ATM p.Phe680=

c.2040C>T · rs587780855 · VCV136436

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.7	GERP -1.2, phastCons 1
Overall
CADD	12.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00517% European (non-Finnish) · 61/1,180,004 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00409% 66/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,344
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Admixed American	0.00167%	60,002
African / African-American	0.00133%	74,920

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.Phe680=
Coding: c.2040C>T
MANE Select: NM_000051
dbSNP: rs587780855
Type: single nucleotide variant
Location: chr11:108253955 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 680: a UniProt-annotated variant site (in at); a UniProt-annotated variant site (in at; uncertain significance)

Full ATM 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: ataxia telangiectasia hereditary breast carcinoma

Similar variants

ATM p.Phe680Leu Uncertain significance ★ ⚠ same residue
ATM c.1607+1G>T Pathogenic ★★★ same condition
ATM c.2251-4A>G Likely pathogenic ★★★ same condition
ATM c.2466+5G>C Likely pathogenic ★★★ same condition
ATM c.3078-1G>A Pathogenic ★★★ same condition
ATM c.332-1G>A Pathogenic ★★★ same condition
ATM c.4909+1G>A Pathogenic ★★★ same condition
ATM c.496+5G>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/atm-p-phe680 (accessed [today's date]).

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