11-108244951-A-G

Position:

• chr11-108244951-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):​c.826A>G​(p.Lys276Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 8.65

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.826A>G	p.Lys276Glu	missense_variant	7/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.826A>G	p.Lys276Glu	missense_variant	7/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461142 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726896

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 27, 2022	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 276 of the ATM protein (p.Lys276Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 143025). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 06, 2024	The p.K276E variant (also known as c.826A>G), located in coding exon 6 of the ATM gene, results from an A to G substitution at nucleotide position 826. The lysine at codon 276 is replaced by glutamic acid, an amino acid with similar properties. This variant has been reported in a female patient diagnosed with breast cancer at age 39 (Feliubadaló L et al. Clin Chem, 2021 03;67:518-533). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.826A>G (p.Lys276Glu) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE. A new acceptor site is created/activated, according to SSF and MaxEnt, but its score does not exceed the natural one. Furthermore, the in silico protein effect prediction for this missense variant is inconclusive and there is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 (PMID: 33280026). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2017

This variant is denoted ATM c.826A>G at the cDNA level, p.Lys276Glu (K276E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys276Glu was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Lys276Glu occurs at a position that is conserved across species and is not located in a known functional domain. Based on currently available evidence, it is unclear whether ATM Lys276Glu is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;.
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.91, 0.85
MutPred		0.24		Loss of ubiquitination at K276 (P = 0.0161);Loss of ubiquitination at K276 (P = 0.0161);Loss of ubiquitination at K276 (P = 0.0161);
MVP		0.95
MPC		0.69
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.68
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587782902; hg19: chr11-108115678;