rs587779866

chr11-108331877-A-Cchr11-108331877-A-Gchr11-108331877-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):c.7630-2A>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,150 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ATM NM_000051.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: 7.35

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: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.01722822 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 11, new splice context is: ttcttaccgctaatctctAGaat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108331877-A-C is Pathogenic according to our data. Variant chr11-108331877-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 127447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108331877-A-C is described in Lovd as [Pathogenic]. Variant chr11-108331877-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7630-2A>C		splice_acceptor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7630-2A>C		splice_acceptor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152152 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251132 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135762

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460998 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726852

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

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: 0.0000294

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change affects an acceptor splice site in intron 51 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 (rs587779866, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with breast cancer and ataxia-telangiectasia (AT) (PMID: 9443866, 9887333, 21833744, 25374739, 26681312). 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 IVS51-2A>C and IVS53-2A>C. ClinVar contains an entry for this variant (Variation ID: 127447). Studies have shown that disruption of this splice site results in skipping of exon 52 and activation of a cryptic splice site and introduces a premature termination codon (PMID: 9887333; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2019	Variant summary: ATM c.7630-2A>C, also known as IVS53-2A>C, 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 the canonical 3' acceptor site. Three predict the variant strengthens an alternate intronic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing reporting skipping of exon 54 (60%) and skipping of the first 11 nt of exon 54 (40%) (legacy exon numbering) (Sandoval_1999). The variant allele was found at a frequency of 8e-06 in 251132 control chromosomes. c.7630-2A>C has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia as well as in individuals undergoing multigene panel testing for hereditary cancers (example, Sandoval_1999, Telatar_1998, Susswein_2016, Tsaousis_2019). These data indicate that the variant is very likely to be associated with disease. Nine 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. Based on the evidence outlined above, the variant was classified as pathogenic for Ataxia Telangectasia and ATM associated cancers. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000127447). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 23, 2018	The c.7630-2A>C sequence change is predicted to abolish the splice acceptor site, and affects splicing of exon 52. RNA study has demonstrated that this variant leads to exon skipping (Sandoval et. al., 1999). This variant has been reported in several patients with ataxia-telangiectasia in the homozygous state or compound heterozygous state with another pathogenic variant (Sandoval et. al., 1999; Podralska et. al., 2014). This variant has also been reported in two patients with breast cancer in the heterozygous state (Susswein et. al., 2016). The contribution of this pathogenic sequence change to this patient's AML remains uncertain. Approximately 10% of patients with ataxia telangiectasia due to biallelic ATM mutations develop cancer, mostly of the lymphoid malignancies including Hodgkin's lymphoma, non-Hodgkin's lymphoma, and several forms of leukemia (Boultwood 2001; Taylor et al., 1996). Heterozygous carriers of pathogenic variants in ATM have been associated with increased risk of breast cancer (Tavtigian et. al., 2009). Our interpretation is based on the current understanding of the genetics of ATM-related diseases. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2022	Canonical splice site variant demonstrated to cause aberrant splicing by exon skipping or use of a cryptic splice site (Sandoval et al., 1999; Laake et al., 2000); Identified in the homozygous state or with a pathogenic variant on the opposite allele in multiple unrelated patients with ataxia telangiectasia and has been described as a pathogenic founder variant in individuals of Polish descent (Telatar et al., 1998; Li and Swift, 2000; Mitui et al., 2005; Soukupova et al., 2011; Nespoli et al., 2013; Podralska et al., 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Brand et al., 2018; Dudley et al., 2018; Goidescu et al., 2018; Cybulski et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS53-2A>C; This variant is associated with the following publications: (PMID: 16411093, 27433846, 28843361, 26580448, 30067863, 31159747, 30772474, 31407689, 25525159, 25374739, 9443866, 25614872, 16266405, 10817650, 21833744, 10980530, 29360161, 15039971, 29785153, 29678143, 30293248, 31173646, 31285527, 34199532, 35716007, 9887333, 10330348) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	ATM: PVS1, PS3:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 01, 2022	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS3_MOD, PM3_VSTR , PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 23, 2022	_x000D_ Criteria applied: PVS1, PS3, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 02, 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: 9443866, 9887333, 10330348]. Functional studies indicate this variant impacts protein function [PMID: 9443866, 9887333, 10330348]. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2022	This variant causes an A to C nucleotide substitution at the -2 position of intron 51 splice acceptor site of the ATM gene. This variant has been shown to cause aberrant RNA splicing and result in the absence of ATM protein (PMID: 9887333, 35716007). This variant has been reported in multiple individuals affected with breast cancer cancer (PMID: 26681312, 29360161, 33050356) and pancreatic cancer (PMID: 29360161, 30067863; Peters et al., 2017, DOI: 10.1200/JCO.2017.35.15_suppl.1501). This variant has been reported in over ten individuals affected with ataxia-telangiectasia (PMID: 9887333, 10817650, 25374739, 25614872, 30772474, 33330270, 34199532; DOI:10.1016/j.nerep.2021.100011). This variant has been identified in 4/276934 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	clinical testing	Ambry Genetics	Aug 03, 2022	The c.7630-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 51 in the ATM gene. This alteration has been detected in conjunction with another pathogenic mutation in numerous individuals with ataxia telangiectasia and has been shown to result in aberrant splicing and decreased ATM protein levels (Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Teraoka S et al. Am J Hum Genet. 1999 Jun;64(6):1617-31; Coutinho G et al. Am. J. Med. Genet. A. 2004 Apr;126A:33-40; Soukupova J et al. Neuromolecular Med. 2011 Sep;13:204-11; Nespoli L et al. Case Reports Immunol, 2013 Oct;2013:296827; Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11;). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This mutation has also been identified in multiple individuals with breast cancer, metastatic prostate cancer, and pancreatic adenocarcinoma (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; Dudley B et al. Cancer, 2018 Apr;124:1691-1700; Brand R et al. Cancer, 2018 Sep;124:3520-3527). Of note, this alteration is also designated IVS53-2A>C in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant occurs 2 nucleotides before exon 52 of the ATM gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This mutation is expected to result in incorrect splicing, alteration in the reading frame and a truncated protein. This variant is present in population databases ( rs587779866, <0.01%) and the mutation database ClinVar contains an entry for this variant (Variation ID: 127447/). This particular variant has been reported in the literature in individuals affected with ataxia-telangiectasia and in breast cancer patients (PMID: 988733, PMID: 26681312). An experimental study showed that this variant results in two aberrant forms of the ATM transcript, one in which exon 52 is skipped and another in which the first 11 nucleotides of exons 52 are skipped (PMID: 9887333 ). -

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

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 08-13-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2022	- -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

Colorectal cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Jun 29, 2022

ACMG criteria used to clasify this variant: PVS1, PM2 -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.3

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_AG_spliceai		0.53		Position offset: 13
DS_AL_spliceai		0.91		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779866; hg19: chr11-108202604; COSMIC: COSV105124714; COSMIC: COSV105124714;