ATM p.Ile2064Met

Variant names:

• chr11-108316107-C-G
• rs876659831
• NM_000051.4:c.6192C>G
• ATM p.Ile2064Met

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2BP4

The NM_000051.4(ATM):c.6192C>G (p.Ile2064Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I2064F: Uncertain_significance (ClinVar VariationId 1752118, 1 star); p.I2064= (synonymous): Benign/Likely_benign (ClinVar VariationId 232544, 2 stars); p.I2064N: Uncertain_significance (ClinVar VariationId 950020, 1 star); p.I2064T: Uncertain_significance (ClinVar VariationId 524246, 2 stars); p.I2064V: Uncertain_significance (ClinVar VariationId 3451546, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0380
• Publications: 0 publications found

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ATM Gene-Disease associations (from GenCC):

• ATM-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Natera, Ambry Genetics
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, G2P, Orphanet, Natera, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and obsolete negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Jun 2026]

Classification according to ACMG Germline Pathogenicity v2019

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 4 pathogenic, 6 benign (OR vs. background: 3.5).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATM NM_000051.4	MANE Select	c.6192C>G p.Ile2064Met	missense	Exon 42 of 63	Prot: NP_000042.3
	ATM NM_001351834.2		c.6192C>G p.Ile2064Met	missense	Exon 43 of 64	Prot: NP_001338763.1 UniProt:
	C11orf65 NM_001330368.2		c.641-7036G>C	intron	Intron 6 of 6	Prot: NP_001317297.1

ATM NM_000051.4

MANE Select

HGVSc / HGVSpc.6192C>Gp.Ile2064Met

Exon rankExon 42 of 63

missense

Prot: NP_000042.3

ATM NM_001351834.2

HGVSc / HGVSpc.6192C>Gp.Ile2064Met

Exon rankExon 43 of 64

missense

Prot: NP_001338763.1UniProt: Q13315

C11orf65 NM_001330368.2

HGVSc / HGVSpc.641-7036G>C

Exon rankIntron 6 of 6

intron

Prot: NP_001317297.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATM ENST00000675843.1	MANE Select	c.6192C>G p.Ile2064Met	missense	Exon 42 of 63	Prot: ENSP00000501606.1 UniProt:
	ATM ENST00000452508.7	TSL:1	c.6192C>G p.Ile2064Met	missense	Exon 43 of 64	Prot: ENSP00000388058.2 UniProt:
	ATM ENST00000527805.6	TSL:1	n.*1256C>G	3_prime_UTR	Exon 40 of 61	Prot: ENSP00000435747.2 UniProt:

ATM ENST00000675843.1

MANE Select

HGVSc / HGVSpc.6192C>Gp.Ile2064Met

Exon rankExon 42 of 63

missense

Prot: ENSP00000501606.1UniProt: Q13315

ATM ENST00000452508.7

TSL:1

HGVSc / HGVSpc.6192C>Gp.Ile2064Met

Exon rankExon 43 of 64

missense

Prot: ENSP00000388058.2UniProt: Q13315

ATM ENST00000527805.6

TSL:1

HGVSc / HGVSpn.*1256C>G

Exon rankExon 40 of 61

3_prime_UTR

Prot: ENSP00000435747.2UniProt: E9PIN0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ataxia-telangiectasia syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.73	D
FuncVEP CTI	Benign	0.036
GPN-Star LLR	N/A	-6.5
GPN-Star score	N/A	6.5
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	79/21	polymorphism
MutationAssessor	Uncertain	2.2	M
PhyloP100	Benign	0.038
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.35	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.22
Sift	Benign	0.074	T
Sift4G	Benign	0.080	T
Varity_R	N/A	0.34
VESM-3B	Benign	-6.7

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs876659831;

hg19: chr11-108186834;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar