rs786202148

chr11-108271060-TTAGT-TGATACTA

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_000051.4(ATM):c.2839-3_2839delinsGATACTA variant causes a splice acceptor, coding sequence, intron change involving the alteration of a 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:10
• Conservation: PhyloP100: 7.62

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 13 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.008941228 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.2, offset of 21, new splice context is: ctaatctaatgcttttaaAGgag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-108271061-TAGT-GATACTA is Pathogenic according to our data. Variant chr11-108271061-TAGT-GATACTA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185405.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.2839-3_2839delinsGATACTA		splice_acceptor_variant, coding_sequence_variant, intron_variant	19/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2839-3_2839delinsGATACTA		splice_acceptor_variant, coding_sequence_variant, intron_variant	19/63		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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change affects an acceptor splice site in intron 18 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. Disruption of this splice site has been observed in individuals with ataxia-telangiectasia (PMID: 12815592; Invitae). This variant is also known as IVS20-3del3ins7. ClinVar contains an entry for this variant (Variation ID: 1076780). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 19 (Invitae). This variant disrupts a region of the ATM protein in which other variant(s) (p.Leu950Arg) have been determined to be pathogenic (PMID: 10873394, 12552559, 20678261, 21792198, 27989354). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 07, 2023	Variant summary: ATM c.2839-3_2839delinsGATACTA 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: Five predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251286 control chromosomes (gnomAD). c.2839-3_2839delinsGATACTA has been reported in the literature in an individual affected with Ataxia-Telangiectasia and in an individual affected with early-onset renal cancer and thyroid cancer (Mitui_2003, LaDuca_2017, Hartman_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 06, 2020	This variant impacts the canonical acceptor site at intron 18 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Splicing has been reported as aberrant for this variant (PMID: 12815592). This variant has been reported in an individual affected with Ataxia-Telangiectasia (PMID: 12815592). 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 Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 23, 2017	Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 25, 2017	Lines of evidence used in support of classification: Well-characterized mutation at same position,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 18, 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	Aug 14, 2023	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 27, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2022

Variant disrupting a canonical splice site in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual with ataxia telangiectasia, but the presence of a second pathogenic variant is unclear (Mitui et al., 2003); Observed in an individual with early-onset renal cancer and thyroid cancer (Hartman et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS20-3del4ins7; This variant is associated with the following publications: (PMID: 28152038, 12815592, 32782288) -

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: rs786202148; hg19: chr11-108141788;