rs1555084832

chr11-108271198-GATGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTGT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):c.2922-50_2940del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.13

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 18 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108271198-GATGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTGT-G is Pathogenic according to our data. Variant chr11-108271198-GATGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407642.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.2922-50_2940del		splice_acceptor_variant, coding_sequence_variant, intron_variant	20/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2922-50_2940del		splice_acceptor_variant, coding_sequence_variant, intron_variant	20/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2023	Intronic variant demonstrated activate a cryptic splice acceptor site, leading to the loss of the first 71 nucleotides of exon 20, also denoted exon 22 by alternate numbering, predicted to result in a frameshift and truncated protein (Bartsch et al., 2012); Observed in trans with an ATM frameshift variant in a child with atypical ataxia-telangiectasia (Bartsch et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21893220) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2022	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 14, 2019	This variant causes a 69-nucleotide deletion encompassing the last 50 nucleotides of intron 19 and the first 19 nucleotides of exon 20 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 25, 2023	The c.2922-50_2940del69 intronic pathogenic mutation results from a deletion of 69 nucleotides beginning 50 nucleotides upstream from coding exon 19 and spanning 19 nucleotides into coding exon 19 of the ATM gene. This pathogenic mutation has been reported in conjunction with another pathogenic mutation in the ATM gene in a 9 year old child with ataxia telangiectasia. The c.2922-50_2940del69 mutation leads to the loss of the native splice acceptor site and the activation of a cryptic exonic splice site causing exon skipping (Bartsch O et al. Eur J Med Genet. 2012 Jan;55(1):49-55, Ambry internal data). 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 classified as a disease-causing mutation. -

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This variant results in the deletion of part of exon 20 (c.2922-50_2940del) of the ATM gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 407642). 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. This variant disrupts a region of the ATM protein in which other variant(s) (p.Cys977Tyr) have been determined to be pathogenic (PMID: 34445196; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 09, 2023

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555084832; hg19: chr11-108141925;