NM_000051.4:c.6188G>A

Variant names:

• chr11-108316103-G-A
• rs866290641
• NM_000051.4:c.6188G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000051.4(ATM):​c.6188G>A​(p.Gly2063Glu) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2063A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.22
• Publications: 9 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]

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 34 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 11-108316103-G-A is Pathogenic according to our data. Variant chr11-108316103-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 420012.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.6188G>A	p.Gly2063Glu	missense_variant	Exon 42 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6188G>A	p.Gly2063Glu	missense_variant	Exon 42 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Mar 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2063 of the ATM protein (p.Gly2063Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-telangiectasia (PMID: 10873394, 14654357, 18634022, 31050087). ClinVar contains an entry for this variant (Variation ID: 420012). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Familial cancer of breast Pathogenic:1

May 31, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 09, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G2063E variant in the ATM gene has been reported in the homozygous state in at least two Turkish individuals with ataxia-telangiectasia (A-T); however, their presentation was noted to be distinct from other A-T patients in that it was slowly progressive with normal immune status (Becker-Catania et al., 2000; Buzin et al., 2003; Chun et al., 2003; Sanal et al., 2004). Cell lines from the homozygous A-T patients were reported to be radiosensitive with reduced ATM protein levels and 35% kinase activity (Becker-Catania et al., 2000; Chun et al., 2003; Butch et al., 2004). However, an in vitro functional study classified this variant as ‘operationally neutral’ with normal protein expression and normal ATM kinase activity (Mitui et al., 2009). The G2063E variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. The G2063E variant occurs at a position that is conserved across species and is located in the FAT domain (Stracker et al., 2013). Based on currently available evidence, we consider G2063E to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G2063E variant (also known as c.6188G>A), located in coding exon 41 of the ATM gene, results from a G to A substitution at nucleotide position 6188. The glycine at codon 2063 is replaced by glutamic acid, an amino acid with similar properties. In one functional study, this alteration had normal kinase and radiosensitivity activity (Mitui M et al. Hum Mutat, 2009 Jan;30:12-21). However, this alteration was also identified in the homozygous state in multiple individuals diagnosed with ataxia telangiectasia (Becker-Catania SG et al. Mol Genet Metab, 2000 Jun;70:122-33; Sun X et al. J Pediatr, 2002 Jun;140:724-31; Chun HH et al. Mol Genet Metab, 2003 Dec;80:437-43). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		9.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.81		Loss of catalytic residue at A2062 (P = 0.039);Loss of catalytic residue at A2062 (P = 0.039);
MVP		0.93
MPC		0.65
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.85
Mutation Taster		=3/97	disease causing

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: rs866290641; hg19: chr11-108186830; COSMIC: COSV53728535; COSMIC: COSV53728535;