rs747855862

chr11-108235669-G-Achr11-108235669-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):c.332-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ATM NM_000051.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.15

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.017882455 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108235669-G-A is Pathogenic according to our data. Variant chr11-108235669-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 231535.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.332-1G>A		splice_acceptor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.332-1G>A		splice_acceptor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249988 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135310

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: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Nov 22, 2022	The ATM c.332-1G>A variant is predicted to create an NMD-escaping transcript resulting in a loss of part of the HEAT repeat domain (PVS1_strong). This variant has been observed in a compound heterozygous state (confirmed) in one individual with Ataxia-Telangiectasia (PMID: 10980530, PM3_strong). This variant is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 09, 2024	This variant is considered 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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2018	This pathogenic variant is denoted ATM c.332-1G>A or IVS4-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 4 of the ATM gene. A splicing assay reportedly demonstrated that this variant, also defined as IVS6-1G>A using alternate numbering, results in the skipping of the adjacent exon (Laake 2000). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. ATM c.332-1G>A was observed in trans with another ATM variant in an individual with Ataxia-Telangiectasia (Laake 2000). Based on currently available evidence, we consider this variant to be likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Ataxia-telangiectasia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2022

Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 10980530). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 10980530; Invitae). ClinVar contains an entry for this variant (Variation ID: 231535). This variant is also known as IVS6-1 G>A. This variant is present in population databases (rs747855862, gnomAD 0.005%). This sequence change affects an acceptor splice site in intron 4 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2022

The c.332-1G>A pathogenic intronic variant results from a G to A substitution one nucleotide upstream from coding exon 4 of the ATM gene. This alteration has been detected in an individual with ataxia-telangiectasia confirmed in trans with another ATM pathogenic mutation, and RNA analysis of this alteration showed skipping of exon 5 leading to an in-frame deletion of 165 base pairs or 55 amino acids (Laake K et al. Hum. Mutat. 2000 Sep; 16(3):232-46). Another study detected this alteration in 0/3030 patients with pancreatic cancer, 1/53105 controls from the ExAC population database, and 0/123136 controls from the gnomAD population database (Hu C et al. JAMA. 2018 06;319:2401-2409). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	30
Dann	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.93		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: rs747855862; hg19: chr11-108106396;