11-108250861-C-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.1396C>T(p.Gln466Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000248 in 1,613,914 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q466Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.54

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 11-108250861-C-T is Pathogenic according to our data. Variant chr11-108250861-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 233553.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.1396C>T	p.Gln466Ter	stop_gained	10/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1396C>T	p.Gln466Ter	stop_gained	10/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152060 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 AF: 0.00000205 AC: 3 AN: 1461854 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74276

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 14, 2020	Variant summary: ATM c.1396C>T (p.Gln466X) 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 have been classified as pathogenic by our laboratory (e.g. c.3372C>G p.Tyr1124X , c.3663G>A p.Trp1221X). The variant was absent in 251410 control chromosomes (gnomAD). c.1396C>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Buzin_2003, Jackson_2016) and in an individual with breast cancer (Mei-Lu_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 04, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 233553). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 12552559). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln466*) 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). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This variant changes 1 nucleotide in exon 10 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in the compound heterozygous state in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 12552559, 26896183), indicating that this variant contributes to disease. This variant has also been reported in individuals affected with breast cancer (PMID: 30128536, 35365198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 2021	The p.Q466* pathogenic mutation (also known as c.1396C>T), located in coding exon 9 of the ATM gene, results from a C to T substitution at nucleotide position 1396. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This truncating mutation was seen in conjunction with pathogenic variants in ATM in individuals diagnosed with ataxia-telangiectasia (Buzin CH et al, Hum. Mutat. 2003 Feb; 21(2):123-31, Jackson TJ et al. Dev Med Child Neurol, 2016 07;58:690-7). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2017

This pathogenic variant is denoted ATM c.1396C>T at the cDNA level and p.Gln466Ter (Q466X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the compound heterozygous state in an individual with ataxia-telangiectasia (Buzin 2003) 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	36
Dann	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96, 0.97
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876660485; hg19: chr11-108121588; COSMIC: COSV53739627; COSMIC: COSV53739627;