rs730881310

chr11-108302847-TTCTA-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_000051.4(ATM):c.5320-5_5320-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00000275 in 1,454,692 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.14

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 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.019190928 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of 7, new splice context is: aatccctttcttgtttttAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108302847-TTCTA-T is Pathogenic according to our data. Variant chr11-108302847-TTCTA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5320-5_5320-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5320-5_5320-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454692 Hom.: 0 AF XY: 0.00000276 AC XY: 2 AN XY: 724248

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2023	This sequence change affects a splice site in intron 35 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 8845835, 14695534, 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 IVS37-5delTCTA or c.5320del7. ClinVar contains an entry for this variant (Variation ID: 181881). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 14695534; 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	Mar 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2020	Variant summary: ATM c.5320-5_5320-2delTCTA 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 a 3' acceptor site. Four predict the variant creates a 3' acceptor site. The variant was absent in 249996 control chromosomes. c.5320-5_5320-2delTCTA has been reported in the literature in individuals affected with Ataxia-Telangiectasia or breast cancer (Gilad_1996, Eng_2004, Susswein_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Gilad_1996). Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 25, 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, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 14, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 05, 2022	This variant deletes 4 nucleotides in intron 35 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study (PMID: 14695534) has shown that this variant leads to the use of a cryptic splice acceptor site, resulting in a deletion of the first 7 nucleotides of exon 36 (also known as exon 38 in the literature). This variant is expected to create a frameshift and premature translation stop signal, resulting in an absent or non-functional protein product. This variant (also known as 5320del7 and IVS37-5delTCTA in the literature) has been reported in individuals affected with ataxia-telangiectasia (PMID: 8845835, 14695534). There was no detectable ATM protein expression in lymphoblastoid cell lines isolated from at least one affected individual (PMID: 14695534). This variant has also been reported in an individual affected with breast cancer (PMID: 26681312). This variant has not been identified 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 19, 2022	The c.5320-5_5320-2delTCTA (also known as IVS37-5delTCTA) intronic pathogenic mutation, located upstream of coding exon 35 in the ATM gene, results from a deletion of 4 nucleotides at positions c.5320-5 to c.5320-2. This mutation (designated as 5320del7) has been observed in multiple individuals with a diagnosis of ataxia-telangiectasia (A-T) (Gilad S et al, Hum. Mol. Genet. 1996 Apr; 5(4):433-9, Eng L et al, Hum. Mutat. 2004 Jan; 23(1):67-76). A-T individuals with at least one copy of this mutation are reported to have no detectable ATM protein (Eng L et al, Hum. Mutat. 2004 Jan; 23(1):67-76). The c.5320-5_5320-2delTCTA mutation has also been reported to cause aberrant splicing that results in the removal of 7 coding nucleotides from coding exon 35, and a transcript that is expected to trigger nonsense-mediated mRNA decay (Eng L et al, Hum. Mutat. 2004 Jan; 23(1):67-76). RNA studies have demonstrated that this alteration results in the same aberrant splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.73		Position offset: 13
DS_AL_spliceai		0.99		Position offset: 6

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881310; hg19: chr11-108173574;