rs1131691154

chr11-108268026-A-Gchr11-108268026-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_000051.4(ATM):c.2639-384A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.000039 (0 hom., cov: 32)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -1.98

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 10 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108268026-A-G is Pathogenic according to our data. Variant chr11-108268026-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108268026-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2639-384A>G		intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2639-384A>G		intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

Gnomad4 AFR AF: 0.000121

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

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2021	Variant summary: ATM c.2639-384A>G alters a non-conserved nucleotide located deep within intron 17 of the ATM gene. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic intronic 5' splice donor site. In alignment with the computational predictions, at least two publications report experimental evidence that this variant affects mRNA splicing by activating a cryptic intronic 3' splice acceptor site in addition to the cryptic intronic 5' splice donor site, resulting in the insertion of a 58 bp pseudoexon exon in the transcript (Nakamura_2012, Fievet_2018). This corresponds to a transcript named r.2638_2639ins[2639442_2639385] as determined by RNA sequencing and is predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, p.(Gly880Glufs*15) (Fievet_2018), which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 31396 control chromosomes (gnomAD). c.2639-384A>G has been reported in the literature in compound heterozygosity with another large genomic deletion in two individuals affected with Ataxia-Telangiectasia from a Japanese family (Nakamura_2012). These data indicate that the variant may be associated with disease. Three 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 likely pathogenic. One submitter cites overlapping evidence utilized in the context of this evaluation further supported by internal data (not presented) corroborating the reported splicing impact. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change falls in intron 17 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 (no rsID available, gnomAD 0.01%). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 22006793, 31050087, 34453918). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 429070). Studies have shown that this variant results in in retention of 58 bases from intron 17 (also known as intron 18) and introduces a premature termination codon (PMID: 22006793, 31050087; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 2022	The c.2639-384A>G pathogenic intronic mutation results from an A to G substitution 384 nucleotides upstream from coding exon 17 in the ATM gene. This alteration has been detected in conjunction with pathogenic ATM variants in individuals affected with ataxia-telangiectasia (Nakamura K et al. Hum. Mutat. 2012 Jan; 33(1):198-208, Fiévet A et al. Hum. Mutat., 2019 10;40:1713-1730, Gu C et al. Clin Chim Acta, 2021 Dec;523:6-9). RNA studies have shown that this alteration creates a cryptic splice donor site and leads to the insertion of a 58-bp pseudoexon into the transcript, which is anticipated to result in nonsense mediated RNA decay (Nakamura K et al. Hum. Mutat. 2012 Jan; 33(1):198-208, Fiévet A et al. Hum. Mutat., 2019 10;40:1713-1730, 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	Jan 04, 2024	This variant causes an A>G nucleotide substitution at the -384 position of intron 17 of the ATM gene. Functional RNA studies have shown that this variant causes retention of 58 base pairs from intron 17, creating a frameshift and premature translation stop signal (PMID: 22006793, 31050087). This variant has been reported in the compound heterozygous state with known pathogenic ATM variants in individuals affected with autosomal recessive ataxia-telangiectasia, indicating that this variant contributes to disease (PMID: 22006793, 31050087, 34453918). This variant has also been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

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 has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22006793, 31050087, 34453918]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 22006793, 31050087, 34453918]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 09, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	22
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		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: rs1131691154; hg19: chr11-108138753;