rs753961188

Positions:

• chr11-108347347-C-CT

Variant summary

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

The NM_000051.4(ATM):​c.8655dup​(p.Val2886CysfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,453,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.44

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]

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 11-108347347-C-CT is Pathogenic according to our data. Variant chr11-108347347-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 420694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.8655dup	p.Val2886CysfsTer10	frameshift_variant	59/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8655dup	p.Val2886CysfsTer10	frameshift_variant	59/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250320 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135326

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: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1453714 Hom.: 0 Cov.: 29 AF XY: 0.00000691 AC XY: 5 AN XY: 723710

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: 0.0000562

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2019	This duplication of one nucleotide in ATM is denoted c.8655dupT at the cDNA level and p.Val2886CysfsX10 (V2886CfsX10) at the protein level. The normal sequence, with the base that is duplicated in brackets, is AACT[dupT]GTAC. The duplication causes a frameshift which changes a Valine to a Cysteine at codon 2886, and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.8655dupT, also described as c.8653_8654insT using alternate nomenclature, has been reported in the compound heterozygous state with an ATM nonsense variant in a child with clinical features of Ataxia-telangiectasia (Barbaro 2017). Based on currently available evidence, we consider this to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 13, 2023	- -

Familial cancer of breast Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 05, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Ataxia-telangiectasia syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Val2886Cysfs*10) 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 (rs753961188, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 27873105). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.8653_8654insT. ClinVar contains an entry for this variant (Variation ID: 420694). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 12, 2020	This variant (also known as c.8653_8654insT) inserts 1 nucleotide in exon 59 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a child affected with autosomal recessive ataxia-telangiectasia in compound heterozygous state with other pathogenic variant (PMID: 27873105), indicating that this variant contributes to disease.This variant has been identified in 5/250320 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	Oct 19, 2021	The c.8655dupT pathogenic mutation, located in coding exon 58 of the ATM gene, results from a duplication of T at nucleotide position 8655, causing a translational frameshift with a predicted alternate stop codon (p.V2886Cfs*10). This alteration has been identified in individuals diagnosed with pancreatic, thyroid, kidney, breast and prostate cancers (Hu C et al. JAMA, 2018 06;319:2401-2409; Hartman TR et al. Sci Rep, 2020 08;10:13518; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 28, 2020

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Val2886Cysfs*10 variant was identified in the literature in a compound heterozygous state in a child affected with ataxia-telangiectasia (Barbaro 2016). The variant was also identified in dbSNP (ID: rs753961188) as "With Pathogenic allele" and ClinVar (classified as pathogenic by Invitae, Color and Ambry Genetics; and as likely pathogenic by GeneDx). The variant was not identified in the LOVD 3.0 database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.8655dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2886 and leads to a premature stop codon at position 2895. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs753961188; hg19: chr11-108218074;