NM_000051.4:c.8246A>G

Variant names:

• chr11-108335939-A-G
• rs779145081
• NM_000051.4:c.8246A>G
• ATM p.Lys2749Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_Supporting

The NM_000051.4(ATM):c.8246A>G (p.Lys2749Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The gene ATM is a tumor suppressor gene (CancerMine: 26 TSG, 31 oncogene, 24 driver citations). The gene ATM is a known oncogene (CancerMine: 26 TSG, 31 oncogene, 24 driver citations). The gene ATM is a cancer driver gene (CancerMine: 26 TSG, 31 oncogene, 24 driver citations). The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,168 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.80). 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.K2749I: Uncertain_significance (ClinVar VariationId 230416, 2 stars); p.K2749= (synonymous): Benign (ClinVar VariationId 3253863, 1 star)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 8.80
• Publications: 8 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 ACGS-UK Somatic Oncogenicity v2025

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 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000015, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 3 pathogenic, 2 benign (OR vs. background: 7.0); Variant does not impact splicing — splice-hotspot path not applicable

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.8246A>G p.Lys2749Arg	missense	Exon 56 of 63	Prot: NP_000042.3
	ATM NM_001351834.2		c.8246A>G p.Lys2749Arg	missense	Exon 57 of 64	Prot: NP_001338763.1 UniProt:
	C11orf65 NM_001330368.2		c.641-26868T>C	intron	Intron 6 of 6	Prot: NP_001317297.1

ATM NM_000051.4

MANE Select

HGVSc / HGVSpc.8246A>Gp.Lys2749Arg

Exon rankExon 56 of 63

missense

Prot: NP_000042.3

ATM NM_001351834.2

HGVSc / HGVSpc.8246A>Gp.Lys2749Arg

Exon rankExon 57 of 64

missense

Prot: NP_001338763.1UniProt: Q13315

C11orf65 NM_001330368.2

HGVSc / HGVSpc.641-26868T>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.8246A>G p.Lys2749Arg	missense	Exon 56 of 63	Prot: ENSP00000501606.1 UniProt:
	ATM ENST00000452508.7	TSL:1	c.8246A>G p.Lys2749Arg	missense	Exon 57 of 64	Prot: ENSP00000388058.2 UniProt:
	C11orf65 ENST00000615746.4	TSL:1	c.*1197-647T>C	intron	Intron 11 of 12	Prot: ENSP00000483537.1 UniProt:

ATM ENST00000675843.1

MANE Select

HGVSc / HGVSpc.8246A>Gp.Lys2749Arg

Exon rankExon 56 of 63

missense

Prot: ENSP00000501606.1UniProt: Q13315

ATM ENST00000452508.7

TSL:1

HGVSc / HGVSpc.8246A>Gp.Lys2749Arg

Exon rankExon 57 of 64

missense

Prot: ENSP00000388058.2UniProt: Q13315

C11orf65 ENST00000615746.4

TSL:1

HGVSc / HGVSpc.*1197-647T>C

Exon rankIntron 11 of 12

intron

Prot: ENSP00000483537.1UniProt: Q8NCR3-1

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152168	Cov:32
GnomAD2 exomes	AF: 0.00	AC:0	Hom:	AN:251016	Cov:
GnomAD4 exome Warning	AF: 0.00000753	AC:11	Hom:0	AN:1459896	Cov:30
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152168	Cov:32

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41956	0.00	0	66880
SCHEMA(Schizophrenia)	0.0000258	2	77658	0.00	0	139310

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Ataxia-telangiectasia syndrome (1)
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.072
GPN-Star LLR	N/A	-5.6
GPN-Star score	N/A	5.6
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.59	D
Mutation Taster	N/A	28/72	disease causing
MutationAssessor	Benign	1.3	L
PhyloP100	Pathogenic	8.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.084	T
Varity_R	N/A	0.41
VESM-3B	Benign	-4.9

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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: rs779145081;

hg19: chr11-108206666;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar