11-108251073-G-T

Position:

• chr11-108251073-G-T

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3 PM2_Supporting PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The ATM c.1607+1G>T canonical splice variant is predicted to result in a truncated protein that disrupts a critical functional domain (PVS1_Strong). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMIDs: 10330348, 1712434, 9450906, 19691550, PM3_VeryStrong). This variant has a GnomAD (v2.1.1) allele frequency of 0.0009% (NFE) which is below the ATM PM2 threshold of 0.001% (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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA348209/MONDO:0016419/020

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.44

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 7 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.1607+1G>T		splice_donor_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1607+1G>T		splice_donor_variant			NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250010 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461714 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change affects a donor splice site in intron 10 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with ataxia telangiectasia (PMID: 10330348, 17124347). 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 IVS12+1G>T. ClinVar contains an entry for this variant (Variation ID: 220555). Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 10330348). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9443866, 9450906; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2023	Variant summary: ATM c.1607+1G>T 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: Three predict the variant abolishes a 5' splicing donor site. One publication reported that the variant resulted in intron retention in a patient derived lymphoblastoid cell line (LCL), which had the variant in homozygous state (Teraoka_1999). The variant allele was found at a frequency of 8e-06 in 250010 control chromosomes (gnomAD). c.1607+1G>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Teraoka_1999, Chessa_2009, Prodosmo_2013). These data indicate that the variant is likely to be associated with disease. Publications reported the lack of ATM protein on western-blot of cells derived from homozygous patients (Teraoka_1999, Prodosmo_2013). Six submitters, including an expert panel (ClinGen), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=5, including the ClinGen Expert panel) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 16, 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, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 16, 2022	The ATM c.1607+1G>T canonical splice variant is predicted to result in a truncated protein that disrupts a critical functional domain (PVS1_Strong). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMIDs: 10330348, 1712434, 9450906, 19691550, PM3_VeryStrong). This variant has a GnomAD (v2.1.1) allele frequency of 0.0009% (NFE) which is below the ATM PM2 threshold of 0.001% (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	Baylor Genetics	Aug 05, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 03, 2023	This variant causes a G to T nucleotide substitution at the +1 position of intron 10 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have reported that this variant (also known as IVS12+1G>T in the literature) leads to the activation of a cryptic splice site 201 basepair upstream (PMID: 9450906) or the retention of intron 10 (PMID: 10330348). Both mutant transcripts are expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 9443866, 9450906, 10330348, 19691550, 23454770). This variant has been identified in 2/250010 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	Nov 20, 2023	The c.1607+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 9 of the ATM gene. This alteration has been detected in multiple homozygous and compound heterozygous individuals of Italian descent with ataxia telangiectasia (A-T) (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31; Magliozzi M et al. Dis. Markers 2006; 22(4):257-64; Telatar M et al. Am. J. Hum. Genet. 1998 Jan; 62(1):86-97; Chessa L et al. Ann. Hum. Genet. 2009 Sep; 73(Pt 5):532-9; Gilad S et al. Hum. Mutat. 1998;11(1):69-75). Furthermore, functional mRNA studies have shown that this alteration leads to aberrant splicing (Gilad S et al. Hum. Mutat. 1998; 11(1):69-75; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31). Further, cells from an individual homozygous for this alteration have been shown to exhibit marked hypersensitivity to DNA damaging agents (i.e. x-rays and potassium bromate), demonstrated by increased chromosomal damage in exposed cells (Mosesso P et al. Mutat Res Genet Toxicol Environ Mutagen. 2018 Dec;836:117-123). Of note, this alteration is also designated as IVS12+1G>T in the published literature. 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. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2019

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9443866, 17124347, 9450906, 19691550, 23454770, 25525159, 10330348) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		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: rs772926890; hg19: chr11-108121800;