NM_000051.4:c.8246_8247delAAinsGG

Variant names:

• chr11-108335939-AA-GG
• NM_000051.4:c.8246_8247delAAinsGG
• ATM p.Lys2749Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM1PM2

The NM_000051.4(ATM):c.8246_8247delAAinsGG (p.Lys2749Arg) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.80). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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); p.K2749R: Uncertain_significance (ClinVar VariationId 407546, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.80
• 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 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 3 pathogenic, 2 benign (OR vs. background: 7.0).
	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.

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.8246_8247delAAinsGG p.Lys2749Arg	missense	N/A	Prot: NP_000042.3
	ATM NM_001351834.2		c.8246_8247delAAinsGG p.Lys2749Arg	missense	N/A	Prot: NP_001338763.1 UniProt:
	C11orf65 NM_001330368.2		c.641-26869_641-26868delTTinsCC	intron	Intron 6 of 6	Prot: NP_001317297.1

ATM NM_000051.4

MANE Select

HGVSc / HGVSpc.8246_8247delAAinsGGp.Lys2749Arg

Exon rankN/A

missense

Prot: NP_000042.3

ATM NM_001351834.2

HGVSc / HGVSpc.8246_8247delAAinsGGp.Lys2749Arg

Exon rankN/A

missense

Prot: NP_001338763.1UniProt: Q13315

C11orf65 NM_001330368.2

HGVSc / HGVSpc.641-26869_641-26868delTTinsCC

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.8246_8247delAAinsGG p.Lys2749Arg	missense	N/A	Prot: ENSP00000501606.1 UniProt:
	ATM ENST00000452508.7	TSL:1	c.8246_8247delAAinsGG p.Lys2749Arg	missense	N/A	Prot: ENSP00000388058.2 UniProt:
	C11orf65 ENST00000615746.4	TSL:1	c.*1197-648_*1197-647delTTinsCC	intron	Intron 11 of 12	Prot: ENSP00000483537.1 UniProt:

ATM ENST00000675843.1

MANE Select

HGVSc / HGVSpc.8246_8247delAAinsGGp.Lys2749Arg

Exon rankN/A

missense

Prot: ENSP00000501606.1UniProt: Q13315

ATM ENST00000452508.7

TSL:1

HGVSc / HGVSpc.8246_8247delAAinsGGp.Lys2749Arg

Exon rankN/A

missense

Prot: ENSP00000388058.2UniProt: Q13315

C11orf65 ENST00000615746.4

TSL:1

HGVSc / HGVSpc.*1197-648_*1197-647delTTinsCC

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr11-108206666;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar