rs730881386

Positions:

• chr11-108365324-G-A
• chr11-108365324-G-C
• chr11-108365324-G-T

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.8988-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.25

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]

ATM (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.41184166 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of -48, new splice context is: cagattttcttattcccaAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108365324-G-A is Pathogenic according to our data. Variant chr11-108365324-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108365324-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.8988-1G>A		splice_acceptor_variant, intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8988-1G>A		splice_acceptor_variant, intron_variant			NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 06, 2024	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 07, 2023	- -
Pathogenic, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Ataxia-telangiectasia syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change affects an acceptor splice site in intron 62 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 12552559, 27664052). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 219587). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2022	Variant summary: ATM c.8988-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. A cDNA sequencing assay has found that this variant affects mRNA splicing through the creation of a cryptic splice site, leading to a 13bp deletion which produces a frameshift and premature stop codon (Casadei_2019). The variant was absent in 251362 control chromosomes (gnomAD). c.8988-1G>A has been reported in the literature in individuals affected with prostate and familial cancer (e.g. Casadei_2019, Wu_2020). To our knowledge the variant has not been found in individuals affected with Ataxia-Telangiectasia, however a variant at the same location, c.8988-1G>C, has been reported in an individual affected by the disease (Teraoka_1999). Seven assessments for this variant have been submitted to ClinVar after 2014. Six submitters classified the variant as pathogenic and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2024	Canonical splice site variant demonstrated to result in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 31843900); Not observed at significant frequency in large population cohorts (gnomAD); Identified in individual(s) with ATM-related cancer in published literature (PMID: 31948886); This variant is associated with the following publications: (PMID: 38854136, 31843900, 31948886, 38898688) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 25, 2023	This variant causes a G to A nucleotide substitution at the canonical -1 position of intron 62 splice acceptor site of the ATM gene. This variant has been reported in a family affected with ATM-related cancers (PMID: 31843900). A functional study using RNA from the carrier individual has shown that this variant disrupts RNA splicing due to the activation of a cryptic splice acceptor site and results in a frameshift and premature truncation (PMID: 31843900). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same position, c.8988-1G>C, is known to be disease-causing due to its disruptive impact on RNA splicing (Clinvar variation ID: 181987). 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	Nov 01, 2022	The c.8988-1G>A pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 62 of the ATM gene. A similar alteration, c.8988-1G>C (also designated as IVS64-1G>C in the published literature), has been identified in two compound heterozygous patients with ataxia-telangiectasia and has been reported to result in activation of a cryptic acceptor site, leading to a deletion of 13 nucleotides (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31. Mitui M et al. Hum. Mutat. 2003 Jul; 22(1):43-50). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.64		Position offset: 14
DS_AL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881386; hg19: chr11-108236051;