11-108227691-C-T

Position:

• chr11-108227691-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000051.4(ATM):​c.67C>T​(p.Arg23Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,402 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. R23R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 3.06

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 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1658 pathogenic variants in the truncated region.
• PP5: Variant 11-108227691-C-T is Pathogenic according to our data. Variant chr11-108227691-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 232248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108227691-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.67C>T	p.Arg23Ter	stop_gained	2/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.67C>T	p.Arg23Ter	stop_gained	2/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251364 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461402 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727028

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PM3_VSTR -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 05, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Ataxia-telangiectasia syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 11, 2022	Variant summary: ATM c.67C>T (p.Arg23X) 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. The variant allele was found at a frequency of 2e-05 in 251364 control chromosomes (gnomAD). c.67C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (examples: Amirfar_2021 and Jackson_2016). These data indicate that the variant is very likely associated with disease. Jackson_2016 demonstrated the homozygous patient's lymphoblastoid cell lines showing ATM protein was present, kinase activity was absent and radiosensitivity was high. Five clinical diagnostic laboratories have submitted 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, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000232248 / PMID: 11756177). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg23*) 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 (rs746235533, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with lymphoma, gastric cancer, and medulloblastoma (PMID: 11756177, 26506520, 29753700). ClinVar contains an entry for this variant (Variation ID: 232248). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in the heterozygous state in individuals with medulloblastoma, lymphoma, prostate, or stomach cancers (PMID: 11756177, 26506520, 29753700, 31214711); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27023146, 11756177, 26506520, 27304073, 26000489, 29753700, 29625052, 31214711, 32888943, 35729272, 26896183, 35273153, 29922827, 34628594, 33547824, 35260754, 36439585, 36451132, 34284872, 36790564, 33309985, 25614872, 23807571) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 12, 2021	This variant changes 1 nucleotide in exon 2 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 reported in individuals affected with mantle cell lymphoma, gastric cancer, medulloblastoma, and breast cancer (PMID: 11756177, 26506520, 29753700, 31214711). This variant has been identified in 5/251364 chromosomes 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	Mar 23, 2022	The p.R23* pathogenic mutation (also known as c.67C>T), located in coding exon 1 of the ATM gene, results from a C to T substitution at nucleotide position 67. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been reported in the tumor and germline of an individual diagnosed with mantle cell lymphoma (Camacho E et al. Blood. 2002 Jan;99(1):238-44), and in a patient with gastric cancer (Huang DS et al. Oncotarget. 2015 Dec;6(38):40953-8). 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	curation	Sema4, Sema4	Dec 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A
Vest4		0.86, 0.77, 0.88
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs746235533; hg19: chr11-108098418; COSMIC: COSV53733622; COSMIC: COSV53733622;