11-108253828-A-AAGATAAAGAAGAACTT

Position:

• chr11-108253828-A-AAGATAAAGAAGAACTT

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.1914_1929dup​(p.Ser644ArgfsTer2) 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. K638K) 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:5
• Conservation: PhyloP100: 2.43

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 11-108253828-A-AAGATAAAGAAGAACTT is Pathogenic according to our data. Variant chr11-108253828-A-AAGATAAAGAAGAACTT is described in ClinVar as [Pathogenic]. Clinvar id is 220196.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.1914_1929dup	p.Ser644ArgfsTer2	frameshift_variant	13/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.1914_1929dup	p.Ser644ArgfsTer2	frameshift_variant	13/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2020	This variant inserts 16 nucleotides in exon 13 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 17, 2022	The c.1914_1929dup16 variant, located in coding exon 12 of the ATM gene, results from a duplication of AGATAAAGAAGAACTT at nucleotide position 1914, causing a translational frameshift with a predicted alternate stop codon (p.S644Rfs*2). 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. -

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 30, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 220196). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser644Argfs*2) in the ATM gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2018

The c.1914_1929dup16 pathogenic variant in the ATM gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1914_1929dup16 variant causes a frameshift starting with codon Serine 644, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Ser644ArgfsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1914_1929dup16 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1914_1929dup16 as a pathogenic variant. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 17, 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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864622415; hg19: chr11-108124555;