rs587778077

chr11-108304829-C-CA

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.5653dup(p.Thr1885AsnfsTer19) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1884T) 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:4 O:1
• Conservation: PhyloP100: 0.0500

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 11-108304829-C-CA is Pathogenic according to our data. Variant chr11-108304829-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 418036.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.5653dup	p.Thr1885AsnfsTer19	frameshift_variant	37/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5653dup	p.Thr1885AsnfsTer19	frameshift_variant	37/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 14, 2023

ClinVar contains an entry for this variant (Variation ID: 418036). This sequence change creates a premature translational stop signal (p.Thr1885Asnfs*19) 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 variant has not been reported in the literature in individuals affected with ATM-related conditions. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2017

This duplication of one nucleotide in ATM is denoted c.5653dupA at the cDNA level and p.Thr1885AsnfsX19 (T1885NfsX19) at the protein level. Using alternate nomenclature, this variant would be defined as ATM 5652dupA. The normal sequence, with the base that is duplicated in brackets, is CACA[dupA]CCCCT. The duplication causes a frameshift, which changes a Threonine to an Asparagine at codon 1885 and creates a premature stop codon at position 19 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 25, 2024

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

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Aug 16, 2018

This sequence variant is a single nucleotide duplication (dupA) in exon 37/63 of the ATM gene and results in an early termination codon 19 amino acids downstream of the frameshift at Thr1885. This variant is predicted to generate a non-functional allele through either the expression of a truncated protein, or a loss of ATM expression due to nonsense mediated decay. This is a previously reported variant (ClinVar) that is absent in control population datasets (ExAC, gnomAD databases) and has not been reported in breast cancer patients in the published literature, to our knowledge. Haploinsufficiency of ATM is a known cause of increased breast cancer risk (PMID 10677309). Thus, we consider this variant to be pathogenic. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

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: rs587778077; hg19: chr11-108175556;