11-108284226-G-C

Variant names:

• chr11-108284226-G-C
• rs730881364
• NM_000051.4:c.3747-1G>C

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.3747-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• 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:5
• Conservation: PhyloP100: 9.28

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.1, offset of 13, new splice context is: tttttacatcttgttataAGgtt. Cryptic site results in frameshift 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 11-108284226-G-C is Pathogenic according to our data. Variant chr11-108284226-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.3747-1G>C		splice_acceptor_variant, intron_variant	Intron 25 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3747-1G>C		splice_acceptor_variant, intron_variant	Intron 25 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3747-1G>C variant is located in the canonical acceptor splice site of intron 25 and it is predicted to disrupt the canonical acceptor and activate a cryptic acceptor in position c.3760. The use of this new acceptor site would produce a shorter exon 26 and the disruption of the reading frame, triggering nonsense mediated decay (NMD) (PVS1). This variant was found in one ataxia-telangiectasia proband (PS4_Supporting; PMID: 22213089). Splicing analysis in carrier RNA shows the loss of the first 13 nucleotides of exon 26 leading to the predicted frameshift and NDM (A. Osorio, unpublished result). Assays performed with lymphoblastoid cell lines of an ataxia-telangiectasia patient showed that the ATM protein was absent and there was a clearly increased radiosensitivity (PS3_Moderate, PMID: 22213089). The variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PS4_Supporting + PS3_Moderate + PM2 (PMID: 33280026). -

Dec 12, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3747-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 25 of the ATM gene. This alteration was identified within a cohort of individuals undergoing ATM genetic testing based on a diagnosis of ataxia-telangiectasia (Verhagen MM et al. Hum Mutat, 2012 Mar;33:561-71). This nucleotide position is highly conserved in available vertebrate species. 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). 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. As such, this alteration is classified as likely pathogenic. -

Ataxia-telangiectasia syndrome Pathogenic:1

Aug 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 181950). Disruption of this splice site has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 21665257, 22213089, 26681312). This sequence change affects an acceptor splice site in intron 25 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). -

not provided Pathogenic:1

Jun 03, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This pathogenic variant is denoted ATM c.3747-1G>C or IVS25-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 25 of the ATM gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in the compound heterozygous state with a second ATM variant in a 16 year old male with Fanconi Anemia (Verhagen 2012; note that a typographical error exists in the presentation of this mutation in Table 1 of this publication). Based on the current evidence, we consider ATM c.3747-1G>C to be pathogenic. -

Familial cancer of breast Pathogenic:1

Jan 22, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 14
DS_AL_spliceai		0.99		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: rs730881364; hg19: chr11-108154953; COSMIC: COSV53726690; COSMIC: COSV53726690;