NM_000051.4:c.5267C>G

Variant names:

• chr11-108301737-C-G
• rs786203369
• NM_000051.4:c.5267C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000051.4(ATM):​c.5267C>G​(p.Thr1756Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 3.27

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13042337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.5267C>G	p.Thr1756Arg	missense_variant	Exon 35 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5267C>G	p.Thr1756Arg	missense_variant	Exon 35 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461462 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2

May 24, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 1756 of the ATM protein (p.Thr1756Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 19781682, 25980754). ClinVar contains an entry for this variant (Variation ID: 186974). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Dec 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4, PM2 -

Apr 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in patients with breast cancer, in an individual with Lynch-syndrome associated cancer and/or polyps, and in unaffected controls (Tavtigian et al., 2009; Tung et al., 2015; Yurgelun et al., 2015; Decker et al., 2017); This variant is associated with the following publications: (PMID: 19781682, 25980754, 28779002, 25186627, 26787654, 26689913) -

Hereditary cancer-predisposing syndrome Uncertain:2

Feb 17, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with arginine at codon 1756 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. In a large international case-control study, this variant was reported in 4/60462 breast cancer cases and 3/53458 controls (PMID: 33471991). In a separate breast cancer case-control study, this variant was reported in a healthy control (PMID: 19781682). This variant was also observed in an individual affected with early onset breast cancer (Color Health internal data) and in an individual affected with Lynch syndrome-associated cancer and/or colorectal polyps who also had a PMS2 variant (PMID: 25980754) that is reported as disease-causing in ClinVar (variation ID: 9245). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1756R variant (also known as c.5267C>G), located in coding exon 34 of the ATM gene, results from a C to G substitution at nucleotide position 5267. The threonine at codon 1756 is replaced by arginine, an amino acid with similar properties. This alteration was detected in 0/4112 breast cancer patients and 1/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration was also detected on a 25-gene panel test in a woman of Western/Northern European ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration was reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J Med Genet, 2016 06;53:366-76). Additionally, this alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast Uncertain:2

Apr 09, 2020

Division of Medical Genetics, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in individuals with breast cancer (Tavtigian 2009, Yurgelun 2015). This variant is not present in population databases (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PM2; PP3 -

Mar 09, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Thr1756Arg variant was identified in 1 of 7582 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer or Lynch Syndrome associated cancer and/or colorectal polyps, and was identified in 1 of 4490 chromosomes from healthy individuals (frequency: (0.00)) (Yurgelun 2015,Tavtigian 2009). In the LS proband, the variant co-occurred with a PMS2 variant (c.137G>T (p.Ser46Ile)), while in the control case that had no personal family history of breast cancer at the time of recruitment, the variant was found to co-occur with another ATM variant (p.W488C) (Yurgelun 2015, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs786203369) “With Uncertain significance allele”, and ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Thr1756Arg residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.73	T;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.12
Sift	Benign	0.43	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.054	B;B
Vest4		0.26
MutPred		0.46		Loss of glycosylation at T1756 (P = 0.0503);Loss of glycosylation at T1756 (P = 0.0503);
MVP		0.74
MPC		0.14
ClinPred		0.49	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203369; hg19: chr11-108172464; COSMIC: COSV105845635; COSMIC: COSV105845635;