rs730881300

Positions:

• chr11-108271101-AC-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.2880del​(p.Leu961CysfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y959Y) 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.992

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 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 11-108271101-AC-A is Pathogenic according to our data. Variant chr11-108271101-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181871.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.2880del	p.Leu961CysfsTer10	frameshift_variant	19/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2880del	p.Leu961CysfsTer10	frameshift_variant	19/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251426 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 25, 2023	This sequence change creates a premature translational stop signal (p.Leu961Cysfs*10) 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 (rs758561876, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast and pancreatic cancers (PMID: 10980530, 17376192, 26483394, 26681312). ClinVar contains an entry for this variant (Variation ID: 181871). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 30, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 08, 2022	This variant deletes 1 nucleotide in exon 19 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: 10980530), breast cancer (PMID: 26681312), and pancreatic cancer (PMID: 26483394). This variant has been identified in 1/251426 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 09, 2020	The c.2880delC pathogenic mutation, located in coding exon 18 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 2880, causing a translational frameshift with a predicted alternate stop codon (p.L961Cfs*10). This alteration has been detected in the compound heterozygous state in two Norwegian individuals with ataxia-telangiectasia (Laake K et al. Hum. Mutat. 2000 Sep;16:232-46; Stray-Pedersen A et al. Clin. Exp. Immunol. 2004 Jul;137:179-86). This alteration has also been reported in a breast cancer patient and a pancreatic cancer patient who underwent hereditary cancer multi-gene panel testing (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25:207-11). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2018

This pathogenic variant is denoted ATM c.2880delC at the cDNA level and p.Leu961CysfsX10 (L961CfsX10) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]TTGC. The deletion causes a frameshift, which changes a Leucine to a Cysteine at codon 961 and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.2880delC has been reported in a compound heterozygous state in individuals with ataxia telangiectasia (Laake 2000, Stray-Pedersen 2004), as well as in an individual with pancreatic cancer (Hu 2016). We therefore consider this variant to be pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 18, 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)		0.0		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: rs730881300; hg19: chr11-108141828;