NM_000051.4:c.1810C>T

Variant names:

• chr11-108252824-C-T
• rs2227922
• NM_000051.4:c.1810C>T
• ATM p.Pro604Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O4_Supporting

The NM_000051.4(ATM):c.1810C>T (p.Pro604Ser) variant causes a missense change involving the alteration of a non-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 0.00224 (AC=3,609) in the gnomAD database across 1,608,310 control chromosomes, including 28 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00897. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P604L: Uncertain_significance (ClinVar VariationId 580035, 1 star); p.P604= (synonymous): Likely_benign (ClinVar VariationId 3649564, 1 star); p.P604R: Uncertain_significance (ClinVar VariationId 2061819, 1 star) The variant has been observed in cBioPortal in 5 samples across 4 studies and 5 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). 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: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (26 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:37 O:2
• Conservation: PhyloP100: 4.58
• Publications: 81 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 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 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=5 | studies=4 | cancer types=5 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.

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.1810C>T p.Pro604Ser	missense	Exon 12 of 63	Prot: NP_000042.3
	ATM NM_001351834.2		c.1810C>T p.Pro604Ser	missense	Exon 13 of 64	Prot: NP_001338763.1 UniProt:

ATM NM_000051.4

MANE Select

HGVSc / HGVSpc.1810C>Tp.Pro604Ser

Exon rankExon 12 of 63

missense

Prot: NP_000042.3

ATM NM_001351834.2

HGVSc / HGVSpc.1810C>Tp.Pro604Ser

Exon rankExon 13 of 64

missense

Prot: NP_001338763.1UniProt: Q13315

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATM ENST00000675843.1	MANE Select	c.1810C>T p.Pro604Ser	missense	Exon 12 of 63	Prot: ENSP00000501606.1 UniProt:
	ATM ENST00000452508.7	TSL:1	c.1810C>T p.Pro604Ser	missense	Exon 13 of 64	Prot: ENSP00000388058.2 UniProt:
	ATM ENST00000531525.3	TSL:1	c.1810C>T p.Pro604Ser	missense	Exon 12 of 30	Prot: ENSP00000434327.3 UniProt:

ATM ENST00000675843.1

MANE Select

HGVSc / HGVSpc.1810C>Tp.Pro604Ser

Exon rankExon 12 of 63

missense

Prot: ENSP00000501606.1UniProt: Q13315

ATM ENST00000452508.7

TSL:1

HGVSc / HGVSpc.1810C>Tp.Pro604Ser

Exon rankExon 13 of 64

missense

Prot: ENSP00000388058.2UniProt: Q13315

ATM ENST00000531525.3

TSL:1

HGVSc / HGVSpc.1810C>Tp.Pro604Ser

Exon rankExon 12 of 30

missense

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00415	AC:631	Hom:2	AN:152010	Cov:32
GnomAD2 exomes	AF: 0.00319	AC:799	Hom:	AN:250226	Cov:
GnomAD4 exome	AF: 0.00205	AC:2978	Hom:26	AN:1456182	Cov:30
GnomAD4 genome	AF: 0.00415	AC:631	Hom:2	AN:152128	Cov:32
TOPMed (Bravo)	AF: 0.00484	AC:1282	Hom:2	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00378	AC:1285	Hom:15	AN:339978	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00854	AC:20	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00400	AC:52	Hom:	AN:12990	Cov:
GenomeAsia100K	AF: 0.00203	AC:7	Hom:	AN:3468	Cov:
Qatari Genome	AF: 0.00360	AC:6	Hom:	AN:1690	Cov:
Turkish Variome	AF: 0.00552	AC:37	Hom:0	AN:6706	Cov:
UK10K	AF: 0.00145	AC:11	Hom:	AN:7562	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000834 *	8	9594	0.000673 *	7	10400
BipEx(Bipolar disorder (including schizoaffective))	0.000880	25	28414	0.00135	39	28834
Epi25(Epilepsy)	0.00231	97	41908	0.00286	191	66820
SCHEMA(Schizophrenia)	0.00454	553	121900	0.00602	1151	191302

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	2	6	Ataxia-telangiectasia syndrome (8)
-	-	7	Hereditary cancer-predisposing syndrome (7)
-	-	7	not provided (8)
-	-	3	Familial cancer of breast (3)
-	1	1	Hereditary breast ovarian cancer syndrome (2)
-	-	1	ATM-related cancer predisposition (1)
-	-	1	ATM-related disorder (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
GPN-Star LLR	N/A	-4.4
GPN-Star score	N/A	4.4
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.47	T
Mutation Taster	N/A	95/5	polymorphism
MutationAssessor	Uncertain	2.4	M
PhyloP100	Uncertain	4.6
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.11	T
Sift4G	Benign	0.27	T
Varity_R	N/A	0.40
VESM-3B	Benign	-3.9

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
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: rs2227922;

hg19: chr11-108123551;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar