rs876660743

Positions:

• chr11-108333940-ATGT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000051.4(ATM):​c.7989_7991delTGT​(p.Val2664del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.05

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000051.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-108333940-ATGT-A is Pathogenic according to our data. Variant chr11-108333940-ATGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233938.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.7989_7991delTGT	p.Val2664del	disruptive_inframe_deletion	54/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7989_7991delTGT	p.Val2664del	disruptive_inframe_deletion	54/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251250 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459324 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2022	In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate loss of protein expression that results in reduced kinase activity (Sandoval 1999, Scott 2002); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21965147, 10817650, 10425038, 11805335, Erdem2019[article], 9887333) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 31, 2021	This variant causes an in-frame deletion of one amino acid in the ATM protein. Functional studies have reported that the variant protein displayed no detectable ATM kinase activity and failed to restore normal radiosensitivity in ATM-deficient cells (PMID: 9887333). This variant (also known as p.Val2662del in the literature) has been reported in the homozygous state or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 9887333, 21965147), as well as in ataxia telangiectasia affected individuals whose second ATM mutation was not reported (PMID: 10425038, 10817650). This variant has been identified in 1/251250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 21, 2024	The c.7989_7991delTGT variant (also known as p.V2664del) is located in coding exon 53 of the ATM gene. This variant results from an in-frame deletion of 3 nucleotides between positions 7989 to 7991. This results in the deletion of a valine residue at codon 2664. This alteration has been described in several patients with ataxia-telangiectasia (A-T), including being detected as a homozygous alteration and in conjunction with another pathogenic ATM mutation (Sandoval N et al. Hum Mol Genet. 1999 Jan;8(1):69-79; Castellvi-Bel S et al. Hum Mutat. 1999;14(2):156-62; Li A and Swift M et al. Am J Med Genet. 2000 May 29;92(3):170-7; Demuth I et al. Neurogenetics. 2011 Nov;12(4):273-82; Chen Z et al. Neurobiol Aging, 2013 Oct;34:2442.e11-7). In addition, functional assays have shown reduced levels of ATM protein expression and an absence of induced ATM kinase activity (Sandoval N et al. Hum Mol Genet. 1999 Jan;8(1):69-79; Scott SP et al. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):925-30). Based on internal structural analysis, this alteration is deleterious and is more untolerated than nearby pathogenic variants (Ambry internal data). Of note, this alteration is also designated as V2662del and V2663del in published literature. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This amino acid position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 01, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9887333, 23726790, 21965147]. Functional studies indicate this variant impacts protein function [PMID: 11805335]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 24, 2023	- -

Ataxia-telangiectasia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

This variant has been observed in individual(s) with ataxia-telangiectasia (A-T) as homozygous or co-occurring with another pathogenic ATM variant, as well as in A-T-affected individuals in whom no second variant was reported (PMID: 9887333, 10425038, 10817650, 21965147). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects ATM function (PMID: 11805335). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 233938). This variant is also known as V2662del, 7989delTGT and Del 3 at codon 2663. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant, c.7989_7991del, results in the deletion of 1 amino acid(s) of the ATM protein (p.Val2664del), but otherwise preserves the integrity of the reading frame. -

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: rs876660743; hg19: chr11-108204667;