NM_000051.4:c.4534G>A

Variant names:

• chr11-108292716-G-A
• rs1060501653
• NM_000051.4:c.4534G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000051.4(ATM):​c.4534G>A​(p.Ala1512Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1512V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 8.78
• Publications: 3 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):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.4534G>A	p.Ala1512Thr	missense	Exon 30 of 63	NP_000042.3
	ATM	NM_001351834.2		c.4534G>A	p.Ala1512Thr	missense	Exon 31 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.4534G>A	p.Ala1512Thr	missense	Exon 30 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.4534G>A	p.Ala1512Thr	missense	Exon 31 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.4534G>A		non_coding_transcript_exon	Exon 30 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2

Feb 21, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1512 of the ATM protein (p.Ala1512Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 407648). 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%. 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 08, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with rectal or renal cancer (Pearlman et al., 2017; Smith et al., 2021); This variant is associated with the following publications: (PMID: 32009247, 32830346, 27978560)

May 24, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:2

May 31, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 1512 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 reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991) and an individual affected with colorectal cancer (PMID: 27978560). 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.

Sep 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1512T variant (also known as c.4534G>A), located in coding exon 29 of the ATM gene, results from a G to A substitution at nucleotide position 4534. The alanine at codon 1512 is replaced by threonine, an amino acid with similar properties. This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This alteration was also detected in cohort of 118 individuals with features suggestive of inherited renal cell carcinoma (Smith PS et al. Genes Chromosomes Cancer, 2021 01;60:5-16). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Uncertain:1

Nov 26, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.29
Sift	Benign	0.044	D
Sift4G	Uncertain	0.049	D
Polyphen		0.94	P
Vest4		0.77
MutPred		0.45		Loss of helix (P = 0.0376)
MVP		0.88
MPC		0.26
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.56
gMVP		0.39
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs1060501653; hg19: chr11-108163443;