chr11-108329088-C-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000051.4(ATM):c.7157C>A(p.Ala2386Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,132 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 7.90

Variant links:

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 links:

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]

C11orf65 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 11-108329088-C-A is Pathogenic according to our data. Variant chr11-108329088-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187391.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr11-108329088-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.7157C>A	p.Ala2386Glu	missense_variant	Exon 49 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.7157C>A	p.Ala2386Glu	missense_variant	Exon 49 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251314

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2386 of the ATM protein (p.Ala2386Glu). This variant is present in population databases (rs786203697, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 31050087, 34759960). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 187391). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. Experimental studies have shown that this missense change affects ATM function (PMID: 31050087, 34759960). 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. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Mar 21, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.7157C>A at the cDNA level, p.Ala2386Glu (A2386E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala2386Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ala2386Glu occurs at a position that is conserved across species and is located in the FAT domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Ala2386Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A2386E variant (also known as c.7157C>A), located in coding exon 48 of the ATM gene, results from a C to A substitution at nucleotide position 7157. The alanine at codon 2386 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was identified as homozygous in two Lebanese siblings with features of ataxia telangiectasia (A-T) and determined to have an “atypical” phenotype. In vitro studies using patient-derived cell lines showed reduced, but not absent, protein levels, reduced response to heat treatment suggesting protein instability, and levels of p53-MCL similar to what is observed for A-T heterozygous carriers (Biagiotti S et al. Front Genet, 2021 Oct;12:759467). This alteration was also detected in a cohort of 36 patients with A-T in another patient with “atypical” phenotype. ATM protein levels were 40% of wild-type, and kinase activity was considered "intermediary" (Fiévet A et al. Hum Mutat, 2019 Oct;40:1713-1730). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;T

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;.

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.036

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.82

Loss of MoRF binding (P = 0.0247);Loss of MoRF binding (P = 0.0247);

MVP

0.89

MPC

0.63

ClinPred

0.96

GERP RS

5.7

Varity_R

0.87

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over