NM_000051.4:c.2250G>T

Variant names:

• chr11-108256340-G-T
• rs1137887
• NM_000051.4:c.2250G>T
• ATM p.Lys750Asn

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PM2PM5PP3_Strong

The NM_000051.4(ATM):c.2250G>T (p.Lys750Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Variant has been reported in ClinVar as Uncertain Significance (★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.K750R: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1788378) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K750E: Uncertain_significance (ClinVar VariationId 919060, 2 stars); p.K750N: Uncertain_significance (ClinVar VariationId 1376781, 1 star); p.K750T: Uncertain_significance (ClinVar VariationId 407469, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• Publications: 19 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

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: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.K750R: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1788378); Other variants at the same amino acid residue (not pathogenic): p.K750E: Uncertain_significance (ClinVar VariationId 919060, 2 stars); p.K750N: Uncertain_significance (ClinVar VariationId 1376781, 1 star); p.K750T: Uncertain_significance (ClinVar VariationId 407469, 2 stars)
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support significant splicing impact — strong computational evidence (PP3); Splicing verdict: pathogenic (Strong).; Germline computational verdict: not pathogenic.

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.2250G>T p.Lys750Asn	missensesplice_region	Exon 14 of 63	Prot: NP_000042.3
	ATM NM_001351834.2		c.2250G>T p.Lys750Asn	missensesplice_region	Exon 15 of 64	Prot: NP_001338763.1 UniProt:

ATM NM_000051.4

MANE Select

HGVSc / HGVSpc.2250G>Tp.Lys750Asn

Exon rankExon 14 of 63

missensesplice_region

Prot: NP_000042.3

ATM NM_001351834.2

HGVSc / HGVSpc.2250G>Tp.Lys750Asn

Exon rankExon 15 of 64

missensesplice_region

Prot: NP_001338763.1UniProt: Q13315

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATM ENST00000675843.1	MANE Select	c.2250G>T p.Lys750Asn	missensesplice_region	Exon 14 of 63	Prot: ENSP00000501606.1 UniProt:
	ATM ENST00000452508.7	TSL:1	c.2250G>T p.Lys750Asn	missensesplice_region	Exon 15 of 64	Prot: ENSP00000388058.2 UniProt:
	ATM ENST00000531525.3	TSL:1	c.2250G>T p.Lys750Asn	missensesplice_region	Exon 14 of 30	Prot: ENSP00000434327.3 UniProt:

ATM ENST00000675843.1

MANE Select

HGVSc / HGVSpc.2250G>Tp.Lys750Asn

Exon rankExon 14 of 63

missensesplice_region

Prot: ENSP00000501606.1UniProt: Q13315

ATM ENST00000452508.7

TSL:1

HGVSc / HGVSpc.2250G>Tp.Lys750Asn

Exon rankExon 15 of 64

missensesplice_region

Prot: ENSP00000388058.2UniProt: Q13315

ATM ENST00000531525.3

TSL:1

HGVSc / HGVSpc.2250G>Tp.Lys750Asn

Exon rankExon 14 of 30

missensesplice_region

Prot: ENSP00000434327.3UniProt: H0YDU7

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:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	48040	0.0000136	1	73800

Showing 1 cohortAllele 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, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	44
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.0082	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Benign	0.055
GPN-Star LLR	N/A	-8.2
GPN-Star score	N/A	8.2
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.17	D
Mutation Taster	N/A	6/94	disease causing
MutationAssessor	Uncertain	2.8	M
PhyloP100	Uncertain	4.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	2.9
REVEL	Uncertain	0.31
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.74
VESM-3B	Benign	-5.6

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
DS_DL_spliceai	Pathogenic	0.99	Position offset: 0
Pangolin (max)	Pathogenic	0.85
Pangolin loss	Pathogenic	0.85	Position offset: 0
SpliceAI score (max)	Pathogenic	0.99	Details are displayed if max score is > 0.2

Showing 6 of 6 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: rs1137887;

hg19: chr11-108127067;

COSMIC: COSV104592317;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar