rs864622389

chr11-108244946-CT-C

Variant summary

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

The NM_000051.4(ATM):c.824del(p.Leu275Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,112 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: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: -0.702

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-108244946-CT-C is Pathogenic according to our data. Variant chr11-108244946-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 220121.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-108244946-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.824del	p.Leu275Ter	frameshift_variant	7/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.824del	p.Leu275Ter	frameshift_variant	7/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250836 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135616

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461112 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726892

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in ATM is a frameshift variant predicted to cause a premature stop codon (p.(Leu275*)) in biologically-relevant-exon 7/63 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (ClinGen). The highest population minor allele frequency in gnomAD v2.1 is 0.002% (2/113,464 alleles) in the European (non-Finnish) population, which is lower than the credible allele frequency for a recessive condtion and ATM-related hereditary cancer. This variant has been reported in at least one family with breast cancer (PMID: 27599564, 29271107). This variant has been detected homozygous and compound heterozygous with a pathogenic variant in individuals with ataxia-telangiectasia (PMID: 9463314, 9887333). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3, PM2_Supporting. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 30, 2023	This sequence change creates a premature translational stop signal (p.Leu275*) 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 0.002%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 9463314, 9887333, 27599564). This variant is also known as 822delT. ClinVar contains an entry for this variant (Variation ID: 220121). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 21, 2016	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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 individuals with breast cancer and segregated with early-onset disease in at least one family (Prodosmo et al., 2016; Decker et al., 2017; Coppa et al., 2018; Dorling 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; Also known as c.822delT; This variant is associated with the following publications: (PMID: 27599564, 29271107, 28779002, 9463314, 31948886, 21792198, 34771661, 29922827, 33471991, 26896183, 9887333) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2021	The c.824delT pathogenic mutation, located in coding exon 6 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 824, causing a translational frameshift with a predicted alternate stop codon (p.L275*). This mutation has been reported in both the homozygous and compound heterozygous states in patients with ataxia telangiectasia (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62(2):334-45; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8(1):69-79), as well as multiple patients with breast cancer (Prodosmo A et al. J. Exp. Clin. Cancer Res., 2016 09;35:135; Coppa A et al. Cancer Med, 2018 01;7:46-55; Dorling et al. N Engl J Med. 2021 02;384:428-439), and an individual with prostate cancer (Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230). Of note, this alteration is also designated as c.822delT in published literature. 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	Color Diagnostics, LLC DBA Color Health	Aug 01, 2022	This variant, also known as c.822delT, deletes 1 nucleotide in exon 7 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 observed in multiple individuals affected with ataxia-telangiectasia, including at least one homozygous case (PMID: 9463314, 9887333). This variant has also been observed in individuals affected with breast cancer, including at least one early-onset case (PMID: 27599564, 28779002, 29271107, 33471991). In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). In a separate case-control study conducted in the UK, this variant was identified in 3/13087 breast cancer cases and absent in 5488 controls (PMID: 28779002). This variant has been identified in 2/250836 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. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 11, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Jan 25, 2024	The c.824del (p.Leu275Ter) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 5 individuals with Ataxia-Telangiectasia (PMID: 26896183, 21792198, 9463314, 9887333). The c.824del (p.Leu275Ter) variant in ATM has a minor allele frequency in gnomAD v2.1.1 of 0.000018 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_VeryStrong) -

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: rs864622389; hg19: chr11-108115673;