rs879254093

chr11-108250928-G-Achr11-108250928-G-Cchr11-108250928-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):c.1463G>A(p.Trp488Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,108 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.44

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108250928-G-A is Pathogenic according to our data. Variant chr11-108250928-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 246090.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.1463G>A	p.Trp488Ter	stop_gained	10/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1463G>A	p.Trp488Ter	stop_gained	10/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2022	Variant summary: ATM c.1463G>A (p.Trp488X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position and a variant resulting in a termination codon at the same position, c.1464G>A (p.Trp488X), have been classified as pathogenic by our laboratory. The variant was absent in 251336 control chromosomes (gnomAD). c.1463G>A has been reported in the literature in individuals affected with Ataxia-Telangiectasia, including at least one case in which it was found to induce nonsense mediated decay (e.g. Cavalieri_2006, Magliozzi_2006, Broccoletti_2011). These data indicate that the variant is likely associated with disease. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2023	This sequence change creates a premature translational stop signal (p.Trp488*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 16941484, 17124347). ClinVar contains an entry for this variant (Variation ID: 246090). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2024	The p.W488* pathogenic mutation (also known as c.1463G>A), located in coding exon 9 of the ATM gene, results from a G to A substitution at nucleotide position 1463. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This mutation has been identified in conjunction with an ATM gross deletion in an Italian individual diagnosed with ataxia-telangiectasia (Cavalieri S et al, Hum. Mutat. 2006 Oct; 27(10):1061). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.1463G>A (p.Trp488*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It appears only once in the gnomAD v2.1.1 non-cancer dataset, specifically in the European (non-Finnish) subpopulation (PM2; http://gnomad.broadinstitute.org). It has been reported in one ataxia-telangiectasia proband in trans with a variant called “c.4436+2702del8526”, which corresponds to the in frame deletion of exons 30 to 34 (32 to 36 in the article’s numbering). This co-occurrence in trans with a likely pathogenic ATM variant awards c.1463G>A with 1 point as per ClinGen SVI Recommendation for in trans Criterion (PM3, PMID: 16941484). Moreover, cDNA studies in the compound heterozygous patient show only a deleted band compatible with the multi-exonic in-frame deletion. The lack of a normal band must mean that the non-deleted allele carrying the c.1463G>A (p.Trp488*) induces NMD, its non-expression demonstrated (PS3_Supporting). The c.1463G>A variant has also been detected in two other ataxia telangiectasia probands (PMID: 20840352, 17124347). In summary, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PM3 + PS3_Supporting (PMID: 33280026). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2017

This variant is denoted ATM c.1463G>A at the cDNA level and p.Trp488Ter (W488X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported patients with classical ataxia-telangiectasia (Cavalieri 2006, Magliozzi 2006, Broccoletti 2011) and is considered pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 16, 2024

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.90, 0.90
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs879254093; hg19: chr11-108121655;