rs587780612

Positions:

• chr11-108247085-CAAAG-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.1027_1030del​(p.Glu343IlefsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 9.26

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 11-108247085-CAAAG-C is Pathogenic according to our data. Variant chr11-108247085-CAAAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135731.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.1027_1030del	p.Glu343IlefsTer2	frameshift_variant	8/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1027_1030del	p.Glu343IlefsTer2	frameshift_variant	8/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 251144 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461536 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74204

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2016	Variant summary: The ATM c.1027_1030delGAAA (p.Glu343Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent ATM 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. p.Trp393X, p.Gln1017X, p.Arg1466X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121026 control chromosomes but has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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.Glu343Ilefs*2) 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 (rs587780612, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348, 10817650, 12552559, 18502988, 21792198, 22213089). This variant is also known as 1024delAAAG, 1027_1030delAAAG, and 1027del4. ClinVar contains an entry for this variant (Variation ID: 135731). 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. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 10, 2014	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 31, 2018	The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Additionally, the variant was found in at least one symptomatic patient, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2023	Frameshift 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; 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; Published functional studies demonstrate reduced levels of protein expression (Becker-Catania et al., 2000); This variant is associated with the following publications: (PMID: 22213089, 19535770, 18502988, 26270727, 28126470, 17985259, 28152038, 10330348, 12552559, 10817650, 21792198, 28873162, 30067863, 30267352, 29506128, 30716324, 29288088, 30980208, 30338439, 26689913, 31871297, 29625052, 29922827, 33858029, 10873394) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 31, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2022	The c.1027_1030delGAAA pathogenic mutation, located in coding exon 7 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 1027 to 1030, causing a translational frameshift with a predicted alternate stop codon (p.E343Ifs*2). This mutation has been reported in numerous patients with classic Ataxia-Telangiectasia (A-T) (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70(2):122-33; Buzin C et al. Hum. Mutat. 2003 Feb;21(2):123-31) and in an individual from a hereditary breast and ovarian cancer cohort (Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). ATM protein expression was found to be entirely absent in one A-T individual with this alteration in conjunction with another ATM mutation (Reiman A et al. Br. J. Cancer. 2011 Aug;105(4):586-91). Of note, this alteration is also designated as 1024delAAAG, c.1024_1027delAAAG, and 1027_1030delAAAG 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	Vantari Genetics	Oct 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 06, 2022	This variant deletes 4 nucleotides in exon 8 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. To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and 1/53460 controls (PMID: 33471991). This variant has been reported in individuals with ataxia-telangiectasia (PMID: 10330348, 10817650, 12552559) with several confirmed in the compound heterozygous state (PMID: 10873394, 21792198, 22213089). This variant has been identified in 8/251144 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	Baylor Genetics	Mar 19, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 11, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

ATM-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

The ATM c.1027_1030delGAAA variant is predicted to result in a frameshift and premature protein termination (p.Glu343Ilefs*2). This variant has previously been reported to be causative for autosomal recessive ataxia telangiectasia (see for example, Teraoka et al. 1999. PubMed ID: 10330348, reported as 1024del; Verhagen et al. 2009. PubMed ID: 19535770). This variant is also reported as pathogenic in an individual with adenocarcinoma of the gastroesophageal junction (Table 1. El Jabbour et al. 2022. PubMed ID: 35078243). This variant is reported in 0.050% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135731/?new_evidence=true). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted 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: rs587780612; hg19: chr11-108117812;