rs886039471

Positions:

• chr11-108326064-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5 PP3_Strong

The NM_000051.4(ATM):​c.6814G>A​(p.Glu2272Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,900 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. E2272Q?) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• Conservation: PhyloP100: 9.52

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108326064-G-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 579169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.6814G>A	p.Glu2272Lys	missense_variant	47/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.6814G>A	p.Glu2272Lys	missense_variant	47/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2018	This variant is denoted ATM c.6814G>A at the cDNA level, p.Glu2272Lys (E2272K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in an individual with childhood acute lymphoblastic leukemia (Gumy Pause 2003). ATM Glu2272Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Glu2272Lys is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether ATM Glu2272Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2016	Variant summary: The ATM c.6814G>A (p.Glu2272Lys) variant involves the alteration of a conserved nucleotide. The variant is present in RAD-3 domain however it is unknown whether the domain is critical to protein function or it involves a critical residue. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 120880 control chromosomes. The variant was found as germline variant in one acute lymphoblastic leukemia sample and as somatic variant in one esophagus sample (Gumy Pause_2003, Lin_2014); however without strong evidence for causality. Because of the absence of sufficient clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 14, 2021	- -

Ataxia-telangiectasia syndrome Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2272 of the ATM protein (p.Glu2272Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of ataxia telangiectasia and with leukemia (PMID: 12673804, 31050087). ClinVar contains an entry for this variant (Variation ID: 265315). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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, criteria provided, single submitter	clinical testing	Counsyl	Aug 08, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 15, 2023	The p.E2272K variant (also known as c.6814G>A), located in coding exon 46 of the ATM gene, results from a G to A substitution at nucleotide position 6814. The glutamic acid at codon 2272 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in conjunction with a pathogenic ATM mutation in an individual with an atypical Ataxia Telangiectasia phenotype (Fiévet A et al. Hum Mutat, 2019 10;40:1713-1730). It was also identified in a pediatric patient with acute lymphoblastic leukemia and a woman with early-onset breast cancer (Gumy Pause et al. Hum. Mutat. 2003 May;21(5):554; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

ATM-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

The ATM c.6814G>A variant is predicted to result in the amino acid substitution p.Glu2272Lys. This variant has been reported in an individual with acute lymphoblastic leukemia and an individual with breast cancer (Table 2, Gumy Pause et al. 2003. PubMed ID: 12673804; Supplement, Lerner-Ellis et al. 2021. PubMed ID: 32885271). It has also been reported along with a second ATM variant in an individual with atypical ataxia-telangiectasia (Patient AT26, Table S2, Fiévet et al. 2019. PubMed ID: 31050087). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108196791-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/265315/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Glu2272Lys variant was identified in 1 of 114 proband chromosomes (frequency: 0.009) from individuals or families with B-precursor ALL, and was not identified in 128 control chromosomes from healthy individuals (Pause 2003). The variant was identified in dbSNP (ID: rs886039471) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), and in LOVD 3.0 (1x as pathogenic (2019)). The variant was identified in control databases in 1 of 30966 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 8728 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, South Asian, and Finnish, populations. The p.Glu2272 residue is conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Glu2272Lys variant may impact the protein; however, this information is not predictive enough to assume 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. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.87		Gain of MoRF binding (P = 0.0033);Gain of MoRF binding (P = 0.0033);
MVP		0.94
MPC		0.61
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs886039471; hg19: chr11-108196791; COSMIC: COSV53744239; COSMIC: COSV53744239;