11-108330233-C-T

Position:

• chr11-108330233-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.7327C>T​(p.Arg2443Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,748 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 0.895

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

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-108330233-C-T is Pathogenic according to our data. Variant chr11-108330233-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108330233-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.7327C>T	p.Arg2443Ter	stop_gained	50/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7327C>T	p.Arg2443Ter	stop_gained	50/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251068 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135686

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000381 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change creates a premature translational stop signal (p.Arg2443*) 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 (rs121434220, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and prostate, breast, and pancreatic cancer (PMID: 8808599, 9887333, 10817650, 14586414, 21833744, 24556621, 26483394, 26822949). ClinVar contains an entry for this variant (Variation ID: 3036). Studies have shown that this premature translational stop signal alters ATM gene expression (PMID: 14970866, 15101044). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): 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: VCV000003036). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 02, 2017	Variant summary: The ATM c.7327C>T (p.Arg2443X) variant results in a premature termination codon, predicted to cause absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This prediction has been confirmed by one study showing that the ATM protein is absent in cells from a patient who carries the variant of interest and a frameshift variant (Prodosmo_2013). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.7517_7520delGAGA, c.8264_8268delATAAG). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple AT patients and is absent in 119996 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 19, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Nov 22, 2023	This variant has been identified by standard clinical testing. female patient with triple-negative breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 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; Observed as heterozygous in individuals with personal or family cancer history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Leongamornlert et al., 2014, Hu et al., 2016, Lhota et al., 2016, Resch et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 19440741, 21833744, 29922827, 24556621, 9443866, 25525159, 15101044, 12497634, 26822949, 28059096, 26483394, 28984303, 12673797, 10817650, 8808599, 9887333, 12697903, 17203191, 29522266, 30322717, 28888541, 33436325, 34680878, 30198223) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Familial cancer of breast Pathogenic:5

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	Institute of Human Genetics, University of Leipzig Medical Center	May 28, 2024	Criteria applied: PVS1,PM2_SUP,PM3_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 31, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Apr 15, 2019	The c.7327C>T variant creates a premature stop codon which is expected to lead to protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in ATM are considered pathogenic (Podralska 2014, Huang 2013). Women who are heterozygous for pathogenic variants in ATM have an increased risk for breast cancer. Men and women who are heterozygous for pathogenic variants in ATM may have an increased risk for pancreatic cancer. There are multiple reported individuals with breast, pancreatic and/or prostate cancer who are heterozygous for the c.7327C>T ATM variant (Leongamornlert 2014, Lhota 2016, Hu 2016). Individuals who are homozygous or compound heterozygous for pathogenic variants in ATM have Ataxia-telangiectasia. The c.7327C>T ATM variant has been reported in multiple individuals with Ataxia-telangiectasia who are compound heterozygous for a second ATM pathogenic variant (Soukupova 2011, Delia 2003, Li 2000, Sandoval 1999, Wright 1996). Thus, this variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2022	This variant changes 1 nucleotide in exon 50 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 breast cancer (PMID: 26822949, 33919281, 34680878), pancreatic cancer (PMID: 26483394), and gastroesophageal junction adenocarcinoma (PMID: 35078243). This variant has also been observed in individuals affected with ataxia-telangiectasia in the homozygous state (PMID: 34337741) or the compound heterozygous state with a pathogenic truncation variant (PMID: 10817650, 23454770). This variant has been identified in 1/251068 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	Apr 07, 2022	The p.R2443* pathogenic mutation (also known as c.7327C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7327. This changes the amino acid from an arginine to a stop codon within coding exon 49. This mutation has been reported in numerous individuals with ataxia-telangiectasia (AT) (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Gutiérrez-Enríquez S et al. Genes Chromosomes Cancer 2004 Jun;40:109-19; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Tariq H et al. J Clin Neurol 2018 Oct;14(4):498-504). This mutation has also been reported in a prostate cancer kindred in which it segregated with disease in an affected brother (Leongamornlert D et al. Br. J. Cancer 2014 Mar;110:1663-72) , in 2/325 high-risk Czech breast cancer patients (Lhota F et al. Clin. Genet. 2016 Oct;90:324-33), and 1/96 individuals with a personal and family history of pancreatic cancer (Hu C. et al. Cancer Epidemiol. Biomarkers Prev. 2016 Jan;25(1):207-11). 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	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 09, 2024	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Carcinoma of pancreas Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

CZECANCA consortium

Mar 04, 2021

- -

Tip-toe gait Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Jun 07, 2023

Gait disorder -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.99
GERP RS		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434220; hg19: chr11-108200960; COSMIC: COSV53724743; COSMIC: COSV53724743;