rs864622416

Positions:

• chr11-108327677-ATG-A

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.7010_7011del​(p.Cys2337SerfsTer35) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C2337C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.41

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 11-108327677-ATG-A is Pathogenic according to our data. Variant chr11-108327677-ATG-A is described in ClinVar as [Pathogenic]. Clinvar id is 220198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7010_7011del	p.Cys2337SerfsTer35	frameshift_variant	48/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7010_7011del	p.Cys2337SerfsTer35	frameshift_variant	48/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 30, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2020	Variant summary: ATM c.7010_7011delGT (p.Cys2337SerfsX35) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251078 control chromosomes (gnomAD). c.7010_7011delGT has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Telatar_1996, Telatar_1998, Li_2000, Buzin_2003, Podralska_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Cys2337Serfs*35) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 8659541, 9443866, 16266405, 25614872). This variant is also known as 7009delTG. ClinVar contains an entry for this variant (Variation ID: 220198). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2022	The c.7010_7011delGT pathogenic mutation, located in coding exon 47 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 7010 to 7011, causing a translational frameshift with a predicted alternate stop codon (p.C2337Sfs*35). This mutation has been well documented in the literature in a compound heterozygous state in multiple individuals with Ataxia Telangiectasia (A-T) (Buzin CH et al. Hum. Mutat. 2003 Feb; 21(2):123-31; Li A et al. Am. J. Med. Genet. 2000 May; 92(3):170-7; Mitui M et al. Ann. Hum. Genet. 2005 Nov; 69(Pt 6):657-64; Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov; 2(6):504-11). 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 25, 2021	This variant deletes 2 nucleotides in exon 48 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 individuals affected with ataxia telangiectasia (PMID: 8659541, 9443866, 16266405, 25614872). This variant has not been identified 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 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; Observed in the heterozygous state in individuals with pancreatic or prostate cancer (Wokolorczyk et al., 2020; Yu et al., 2022); 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; This variant is associated with the following publications: (PMID: 10817650, 8659541, 12969974, 35047863, 25614872, 32875559, 12511424, 25502423, 16266405, 23807571, 12552559, 9443866) -

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: rs864622416; hg19: chr11-108198404;