rs587781558

chr11-108271147-G-Achr11-108271147-G-Cchr11-108271147-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):c.2921+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,342 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 7.71

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 20 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108271147-G-A is Pathogenic according to our data. Variant chr11-108271147-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108271147-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2921+1G>A		splice_donor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2921+1G>A		splice_donor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151710 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251304 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135846

Gnomad AFR exome AF: 0.000123

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461632 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727150

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151710 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74048

Gnomad4 AFR AF: 0.0000242

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2017	Variant summary: The ATM c.2921+1G>A variant involves the alteration of a conserved intronic nucleotide, which 4/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts the removal of an ESE binding site. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121072 (1/40355), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasia. Multiple publications cite the variant in A-T patients that were homozygous or compound heterozygous. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change affects a donor splice site in intron 19 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587781558, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835, 11298136, 12673797, 12815592, 23322442). 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: 141182). Studies have shown that disruption of this splice site results in skipping of exon 19 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 25, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 14, 2023	The ATM c.2921+1G>A variant results in the substitution of a guanine within the consensus splice donor site with an adenine which has been shown to result in splicing defects (PMID: 11298136). This variant has been reported in at least three individuals with ataxia-telangiectasia including in two individuals in a homozygous state and in one individual in a compound heterozygous state (PMID: 8845835; PMID: 12673797). This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000123 in the African/African American population. The c.2921+1G>A variant was identified in trans with a second ATM variant. Based on the available evidence, the c.2921+1G>A variant is classified as pathogenic for ataxia-telangiectasia. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2022	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Garcia-Perez et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS21+1G>A; This variant is associated with the following publications: (PMID: 11382771, 29486991, 28888541, 25525159, 12815592, 10425038, 11298136, 23322442, 10330348, 21445571, 21665257, 12673797, 12552559, 24663073, 27443514, 28152038, 8845835, 26689913, 32832836, 31589614, 32427313, 33280026, 32853339, 33462019, 32782288, 29625052, 29922827, 31214711, 31741144, 31050087, 1300551, 8968760, 34204722, 25614872) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 09, 2019	DNA sequence analysis of the ATM gene demonstrated a sequence change in the canonical splice donor site of intron 19, c.2921+1G>A. This sequence change has been previously described in patients with Ataxia-telangiectasia in both homozygous and compound heterozygous state (Garc?a-P?rez et al., 2001; Gilad et al., 1996 and Jeddane et al., 2013). This sequence change has been described in the gnomAD database with a population frequency of 0.0024% (rs587781558). This sequence change is predicted to affect normal splicing of the ATM gene and result in an abnormal protein. These collective evidences indicate that this sequence change is pathogenic. This sequence change was identified with another likely pathogenic ATM variant in a patient. -
Pathogenic, no assertion criteria provided	clinical testing	Franklin by Genoox	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ATM: PVS1, PM3:Strong, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 29, 2014	This variant disrupts a canonical splice-donor site and interferes with normal ATM mRNA splicing. The frequency of this variant in the general population, 0.00012 (2/16230 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with breast cancer (PMIDs: 12673797 (2003), 21445571 (2011)), and with ataxia-telangiectasia (PMIDs: 8845835 (1996), 12673797 (2003), 12815592 (2003), 23322442 (2013), 30338439 (2019)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2022	The c.2921+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 18 of the ATM gene. This mutation is also designated as IVS21+1G>A and 2839del83 in published literature. This mutation has previously been reported in the literature in clinically affected individuals with ataxia-telangiectasia in both compound heterozygous and homozygous forms (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Castellvi-Bel S et al. Hum. Mutat. 1999;14:156-62; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94). The c.2921+1G>A mutation has also been shown to lead to exon skipping resulting in a frameshift and premature protein truncation (García-Pérez MA et al. Clin. Exp. Immunol. 2001 Mar;123:472-80). RNA studies have demonstrated that this alteration results in the same splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2023	This variant causes a G to A nucleotide substitution at the +1 position of intron 19 of the ATM gene. An RNA study has shown that this variant causes the skipping of exon 19 (also known as exon 21 in the literature), creating a premature translation stop signal in the RNA transcript (PMID: 11298136). The aberrant transcript is expected to result in an absent or non-functional protein product. This variant is also known as IVS21+1G>A and 2839del83 in the literature. This variant has been observed in individuals affected with familial breast cancer (PMID: 33462019, 34204722) and prostate cancer (PMID: 31214711, 32315455, 35652560). This variant has also been reported in homozygous and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 8845835, 11298136, 12673797, 12815592, 23322442, 34337741). This variant has been identified in 6/251304 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.2921+1G>A variant is located in the canonical donor splice site of intron 19, and it is predicted to cause the skipping of exon 19 and disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.000021 (0.002%, 5/236,780 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.000067 (0.006721%, 1/14878 alleles) in the African subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been described in trans with a (likely) pathogenic ATM variant in three ataxia-telangiectasia probands and in homozygosis in two additional ataxia-telangiectasia probands, which awards 4 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong ; PMID: 8968760; PMID: 11298136; PMID: 12815592). Moreover, there is an RNA assay which confirms the deletion of 83bp of exon 19 leading to NMD (PS3_Supporting; PMID: 11298136). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_VeryStrong + PS3_Supporting (PMID: 33280026). -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 18, 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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8845835, 10425038, 12815592, 23322442, 31741144]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2023	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 29, 2016

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 23, 2022

- -

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Feb 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	33
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		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		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: rs587781558; hg19: chr11-108141874; COSMIC: COSV53740769;