Variant rs730881346 details in Genebe, Genetics Data Aggregator

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]

ATM links:

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 11-108257471-T-G is Pathogenic according to our data. Variant chr11-108257471-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.2251-10T>G		intron_variant		ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.2251-10T>G		intron_variant			NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

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:

0.00000800

AC:

AN:

250112

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135302

show subpopulations

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:

0.0000185

AC:

AN:

1459908

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726346

show subpopulations

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:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

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

Alfa

AF:

0.0000617

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 27, 2018	The ATM c.2251-10T>G variant (rs730881346), also known as IVS16-10T>G, is reported in the literature in multiple individuals with ataxia-telangiectasia, both in the homozygous state and in trans to other pathogenic variants (Becker-Catania 2000, Buzin 2003, Stankovic 1998, Telatar 1998). This variant has also been reported in an individual affected with breast cancer (Susswein 2016). The c.2251-10T>G variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 181926), and it is found on only three chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic acceptor splice site, leading to inclusion of nine nucleotides containing a premature stop codon. RNA studies from patient cells containing this variant support this effect on splicing (Teraoka 1999), and immunoblotting performed on cells homozygous for this variant indicate no detectable ATM variant present (Stankovic 1998, Wang 2017). Based on available information, this variant is considered to be pathogenic. References: Becker-Catania SG et al. Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity. Mol Genet Metab. 2000 Jun;70(2):122-33. Buzin CH et al. Comprehensive scanning of the ATM gene with DOVAM-S. Hum Mutat. 2003 Feb;21(2):123-31. Stankovic T et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-45. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Telatar M et al. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet. 1998 Jan;62(1):86-97. Teraoka SN et al. Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet. 1999 Jun;64(6):1617-31. Wang C et al. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib. Transl Oncol. 2017 Apr;10(2):190-196. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: ATM c.2251-10T>G alters a conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site. Two predict the variant abolishes a 3' acceptor site. Experimental evidence in support of these predictions demonstrated the variant to create a novel splice site and cause the insertion of 9 nucleotides eventually leading to truncation of the protein (Teraoka_1999). The variant allele was found at a frequency of 1.1e-05 in 275962 control chromosomes (gnomAD). c.2251-10T>G has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Reiman_2011, Buzin_2003, Becker-Catania_2000, Telatar_1998). The variant has also been reported in individuals affected with breast and pancreatic cancer (Hu_2018, Susswein_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12552559, 10330348, 10873394, 26681312, 21792198, 9443866, 28281021, 29922827, 28182994). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=9) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change falls in intron 14 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs730881346, gnomAD 0.002%). This variant has been observed in individuals with ataxia-telangiectasia and/or breast cancer (PMID: 9443866, 9463314, 10330348, 10873394, 12552559, 26681312). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS16-10T>G or 2249ins9nt. ClinVar contains an entry for this variant (Variation ID: 181926). Studies have shown that this variant alters ATM gene expression (PMID: 9463314, 10873394, 21792198). Studies have shown that this variant results in activation of a cryptic splice site 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	clinical testing	Counsyl	Feb 09, 2017	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 17, 2023	This variant causes a T to G nucleotide substitution at the -10 position of intron 14 of the ATM gene. Splice site prediction tools predict that this variant may create an alternative splice acceptor site. The use of this splice site is predicted to create a premature translation termination signal and is expected to result in an absent or non-functional protein product. Cell lines that are homozygous for this variant are reported to have undetectable ATM protein and autophosphorylation activity (PMID: 28182994). This variant (also known as IVS16-10T>G in the literature) has been reported in the homozygous state and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 9443866, 9463314, 10330348, 10873394, 12552559, 21792198, 34539671). Cells derived from some of these individuals have shown reduced or absent ATM protein levels and undetectable ATM kinase activity (PMID: 10873394, 21792198). This variant has also been reported in individuals affected with breast cancer and pancreatic cancer (PMID: 26681312, 28281021, 28779002, 29922827). This variant has been identified in 3/281524 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 Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 12, 2022	The c.2251-10T>G intronic pathogenic mutation results from a T to G substitution 10 nucleotides upstream from coding exon 14 in the ATM gene. This alteration has been reported in conjunction with a second, pathogenic mutation in multiple individuals diagnosed with ataxia-telangiectasia (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Teraoka SN et al. Am. J. Hum. Genet. 1999 June;64:1617-31; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Campbell C et al. Hum. Mutat. 2003 Jan;21:80-85; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31). In addition, this alteration has been identified in individuals diagnosed with breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 showed 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Apr 22, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 09, 2024	The ATM c.2251-10T>G variant disrupts a canonical splice-acceptor site and interferes with normal ATM mRNA splicing. This variant has been reported in the published literature in individuals with breast cancer (PMIDs: 26681312 (2015), 28779002 (2017)), breast cancer and/or ovarian cancer (PMIDs: 28281021 (2017), 35626031 (2022)), pancreatic cancer (PMIDs: 29922827 (2018), 37345735 (2023)), leukemia (PMIDs: 16014569 (2005), 37450374 (2023)) and lymphopenia (PMID: 34539671 (2021)), as well as in the biallelic state with a second pathogenic variant in individuals with ataxia telangiectasia (PMIDs: 9443866 (1998), 9463314 (1998), 10873394 (2000), 12552559 (2003)). The frequency of this variant in the general population, 0.000023 (3/129008 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper ATM mRNA splicing. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2024	Observed as a single heterozygous variant in individuals with breast, pancreatic, or other cancers (PMID: 28779002, 29922827, 32081490); Functional studies demonstrate abnormal splicing: creation of a new splice acceptor site resulting in the addition of nine nucleotides and subsequent protein truncation (PMID: 9443866, 10330348, External communication with Ambry Genetics); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as ATM IVS16-10T>G; This variant is associated with the following publications: (PMID: 28281021, 29922827, 16014569, 12497634, 10330348, 26681312, 16141195, 9463314, 27304073, 21792198, 28182994, 12673797, 9443866, 28779002, 12552559, 31447099, 35626031, 32081490, 34570182, 34539671, 10873394) -

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2024	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9443866, 9463314, 10330348, 10873394, 12552559]. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

ATM-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2024

The ATM c.2251-10T>G variant is predicted to interfere with splicing. In the literature this variant has been referred to as IVS16-10T>G and 2249ins9nt. This variant has been reported in the homozygous state in an individual with ataxia telangiectasia (Stankovic et al. 1998. PubMed ID: 9463314) and along with a second pathogenic variant in multiple individuals with ataxia telangiectasia (Telatar et al. 1998. PubMed ID: 9443866; Becker-Catania et al. 2000. PubMed ID: 10873394; Stankovic et al. 1998. PubMed ID: 9463314; Buzin et al. 2003. PubMed ID: 12552559). Additionally, this variant has been reported in the heterozygous state in an individual with breast cancer (Table S1, Susswein et al. 2016. PubMed ID: 26681312) and another individual with pancreatic cancer (eTable 3, Hu et al. 2018. PubMed ID: 29922827). cDNA analysis indicates this variant leads to the creation of a novel splice acceptor site and results in premature protein termination (Stankovic et al. 1998. PubMed ID: 9463314; Teraoka et al. 1999. PubMed ID: 10330348). This variant is present in 3 out of 281,524 alleles in the gnomAD database and has been interpreted as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/181926/). Based on the available evidence, we interpret the ATM c.2251-10T>G variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Uncertain

DANN

Benign

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 1

DS_AL_spliceai

0.91

Position offset: 10

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs730881346

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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