rs786204726

Positions:

• chr11-108365104-TTGAC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.8876_8879delACTG​(p.Asp2959fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,822 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.09

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108365104-TTGAC-T is Pathogenic according to our data. Variant chr11-108365104-TTGAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189140.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.8876_8879delACTG	p.Asp2959fs	frameshift_variant	62/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8876_8879delACTG	p.Asp2959fs	frameshift_variant	62/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251380 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461822 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2019	Variant summary: ATM c.8876_8879delACTG (p.Asp2959GlyfsX3) 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. The variant allele was found at a frequency of 1.2e-05 in 251380 control chromosomes (gnomAD). c.8876_8879delACTG has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (Carranza_2017, Mitui_2003). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrate the variant to cause absence of ATM protein expression and to confer intermediate radiosensitivity (Carranza_2017). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=4) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Asp2959Glyfs*3) 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 (rs770704493, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 12815592, 27664052). This variant is also known as 8875_8878delGACT and 8874_8877delTGAC. ClinVar contains an entry for this variant (Variation ID: 189140). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 21, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.8876_8879del (p.Asp2959Glyfs*3) frameshift variant is predicted to result in a premature stop codon that leads to a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0013%, (3/236,852 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0058%, (2/34,246 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been described in trans with the likely pathogenic ATM variant c.8977C>T in an ataxia-telangiectasia proband and in homozygosis in another, which awards 1.5 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3; PMID: 12815592, 27664052). Lymphoblastoid cell lines of the homozygous patient showed no ATM protein expression and intermediate radiosensitivity (PS3_Supporting; PMID: 27664052). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3 + PS3_Supporting (PMID: 33280026). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 14, 2023	The c.8876_8879delACTG pathogenic mutation, located in coding exon 61 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 8876 to 8879, causing a translational frameshift with a predicted alternate stop codon (p.D2959Gfs*3). This mutation has been previously identified in three individuals with ataxia telangiectasia, two of whom carried a second truncating ATM mutation (Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). Of note, this alteration is also designated as 8874_8877delTGAC and 8875_8878delGACT 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	Jan 15, 2020	This variant deletes 4 nucleotides in exon 62 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 identified in 3/251380 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	Dec 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 06, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 25, 2019

This variant has been previously reported as pathogenic [PMID 12815592]. Defects in ATM are the cause of ataxia telangiectasia (AT) [MIM:208900], an autosomal recessive disorder characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. Patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 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; Also known as c.8874_8877delTGAC and c.8875_8878delGACT; This variant is associated with the following publications: (PMID: 28888541, 25479140, 31206626, 29922827, 23807571, 25614872, 36414972, 33280026, 12815592, 27664052) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786204726; hg19: chr11-108235831;