rs587781990

chr11-108335082-T-Achr11-108335082-T-Cchr11-108335082-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000051.4(ATM):c.8124T>A(p.Asp2708Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2708Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.393

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108335080-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 11-108335082-T-A is Pathogenic according to our data. Variant chr11-108335082-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 141760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.8124T>A	p.Asp2708Glu	missense_variant	55/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.8124T>A	p.Asp2708Glu	missense_variant	55/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 2708 of the ATM protein (p.Asp2708Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-telangiectasia (PMID: 16411093, 22071889). ClinVar contains an entry for this variant (Variation ID: 141760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 22071889). This variant disrupts the p.Asp2708 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16941484, 21665257, 21792198, 22071889, 23454770, 23632773, 27913932, 29909963). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2019

The p.D2708E pathogenic mutation (also known as c.8124T>A) is located in coding exon 54 of the ATM gene. This alteration results from a T to A substitution at nucleotide position 8124. The aspartic acid at codon 2708 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration occurs 3 codons upstream of the critical PI3-kinase functional domain and has been reported homozygous in two patients with ataxia-telengiectasia (A-T) (Heinrich T et al. Eur. J. Pediatr. 2006; 165:250-7; Bisgin A et al. Biomed Res Int 2018 May;2018:9647253). This alteration has also been reported in conjunction with a frameshift ATM mutation in another individual with A-T (Micol R et al. J. Allergy Clin. Immunol. 2011 Aug;128(2):382-9.e1; Jacquemin V et al. Eur. J. Hum. Genet. 2012; 20:305-12). In addition, a disease-causing mutation, p.D2708N, has been described at the same codon (Micol R et al. J. Allergy Clin. Immunol. 2011;128(2):382-9; Cavalieri S et al. Ann. Hum. Genet. 2008;72(Pt 1):10-8; Magliozzi M et al. Dis. Markers 2006; 22(4):257-64; Barone G et al. Hum. Mutat. 2009;30(8):1222-30). Functional analyses of p.D2708E and p.D2708N, have demonstrated significant ATM protein underexpression and mislocalization (Jacquemin V et al. Eur. J. Hum. Genet. 2012; 20:305-12). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	0.15
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;.
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.55		Loss of ubiquitination at K2710 (P = 0.0509);Loss of ubiquitination at K2710 (P = 0.0509);
MVP		0.96
MPC		0.56
ClinPred		0.99	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.74

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: rs587781990; hg19: chr11-108205809;