11-108293436-CA-CAA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000051.4(ATM):c.4741dup(p.Ile1581AsnfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,460,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 5.07

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 11 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 11-108293436-C-CA is Pathogenic according to our data. Variant chr11-108293436-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453535.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=6, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4741dup	p.Ile1581AsnfsTer5	frameshift_variant	31/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4741dup	p.Ile1581AsnfsTer5	frameshift_variant	31/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460394 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726614

Gnomad4 AFR exome AF: 0.00

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: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 11, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 453535). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 24951259). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile1581Asnfs*5) 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2017	This duplication of one nucleotide in ATM is denoted c.4741dupA at the cDNA level and p.Ile1581AsnfsX5 (I1581NfsX5) at the protein level. Using alternate nomenclature, this variant has previously been reported as ATM c.47356_4736insA. The normal sequence, with the base that is duplicated in brackets, is CAAAAA[dupA]TCAA. The duplication causes a frameshift which changes an Isoleucine to an Asparagine at codon 1581, and creates a premature stop codon at position 5 of the new reading frame. Although this variant has not, to our knowledge, been reported as a germline variant, it has been reported as a somatic variant in a colorectal tumor (Yu 2015). Based on current evidence, we consider this variant to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 17, 2020	PVS1, PM2 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2022	The c.4741dupA pathogenic mutation, located in coding exon 30 of the ATM gene, results from a duplication of A at nucleotide position 4741, causing a translational frameshift with a predicted alternate stop codon (p.I1581Nfs*5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Apr 20, 2020	This variant inserts 1 nucleotide in exon 31 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, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 24, 2024

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs864622164; hg19: chr11-108164163;