rs587780645

Positions:

• chr11-108365415-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.9079dup​(p.Ser3027LysfsTer36) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L3026L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.88

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108365415-C-CA is Pathogenic according to our data. Variant chr11-108365415-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135788.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.9079dup	p.Ser3027LysfsTer36	frameshift_variant	63/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.9079dup	p.Ser3027LysfsTer36	frameshift_variant	63/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135900

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change results in a frameshift in the ATM gene (p.Ser3027Lysfs*36). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the ATM protein and extend the protein by 5 additional amino acid residues. This variant is present in population databases (rs587780645, gnomAD 0.003%). This frameshift has been observed in individual(s) with ATM-related conditions (PMID: 15039971, 21965147, 26270727). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 9080insA, c.9080dupA, and c.9078_9079insA. ClinVar contains an entry for this variant (Variation ID: 135788). This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 19431188, 19691550). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2022	Variant summary: ATM c.9079dupA (p.Ser3027LysfsX36) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes. c.9079dupA has been reported in the literature in individuals affected with Ataxia-Telangiectasia and related conditions (example, Coutinho_2004, Demuth_2011, Feliubadal_2021). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.9079dup (p.Ser3027Lysfs*36) variant duplicates one nucleotide in the last exon of ATM. It is predicted to create a frame shift and result in an extension of the protein, not triggering nonsense-mediated mRNA decay (NMD). The frame shift after residue 3027 alters the FATC domain, critical for ATM activation as its interaction with the Tip60 histone acetyltransferase allows ATM acetylation and then autophosphorylation (PVS1_Strong, according to the PVS1 algorithm recommended by ACMG/AMP in 2018; PMID: 30192042). This variant appears only once in the gnomAD v2.1.1 non-cancer dataset, specifically in the African subpopulation (PM2; http://gnomad.broadinstitute.org). Moreover, it was detected in two ataxia-telangiectasia probands (PS4_Moderate; PMID: 15039971, 21965147). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1_Strong + PM2 + PS4_Moderate (PMID: 33280026). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 13, 2021	This variant inserts 1 nucleotide in exon 63 of the ATM gene, creating a frameshift in the last coding exon and extending the length of the ATM protein by 5 amino acids. This variant is expected to alter the FATC domain and disrupt the ATM protein function (PMID: 16603769). This variant has been reported in the compound heterozygous state with a second ATM mutation in individuals affected with ataxia telangiectasia (PMID: 15039971, 21965147). This variant has also been reported in individuals affected with colorectal cancer or hereditary breast and ovarian cancer (PMID: 26270727, 28135145). This variant has been identified in 1/251460 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 Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 07, 2022	The c.9079dupA pathogenic mutation, located in coding exon 62 of the ATM gene, results from a duplication of A at nucleotide position 9079, causing a translational frameshift with a predicted alternate stop codon (p.S3027Kfs*36). This pathogenic mutation has been reported in the literature in a compound heterozygous state with a splice site mutation in a Brazilian patient with classical ataxia telangiectasia (Coutinho G et al. Am. J. Med. Genet. A 2004 Apr;126A(1):33-40). In addition to the clinical data presented in the literature, this frameshift occurs near the 3' terminus of ATM and results in the elongation of the protein by 6 amino acids. This mutation alters the sequence of the FATC domain of the ATM protein which has been shown to be necessary for ATM regulation (Jiang XJ et al. Biol. Chem. 2006 Jun;281(23):15741-6). As such, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 09, 2022	ACMG classification criteria: PVS1 strong, PS4 supporting, PM2 moderated, PM3 moderated -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 06, 2024	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15039971, 21965147]. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2018

This duplication of one nucleotide in ATM is denoted c.9079dupA at the cDNA level and p.Ser3027LysfsX36 (S3027KfsX36) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GCTC[dupA]GTGT. The duplication causes a frameshift, which changes a Serine to a Lysine at codon 3027 in the last exon of the gene, and results in an extension of the protein. The last 30 amino acids are replaced by 35 incorrect ones, disrupting the FATC domain (Stracker 2013). ATM Ser3027LysfsX36 has been observed in the compound heterozygous state in individuals with ataxia telangiectasia (Coutinho 2004, Demuth 2011), and in at least one individual with breast cancer (Desmond 2015). Based on the currently available information, we consider this duplication to be a likely pathogenic variant. -

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: rs587780645; hg19: chr11-108236142;