rs876660041

Positions:

• chr11-108331553-ATAATG-A

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.7629_7629+4del variant causes a splice donor, coding sequence change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N2542N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor, coding_sequence
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.69

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012321448 fraction of the gene. No cryptic splice site detected. Exon removal is inframe 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 11-108331553-ATAATG-A is Pathogenic according to our data. Variant chr11-108331553-ATAATG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 232873.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.7629_7629+4del		splice_donor_variant, coding_sequence_variant	51/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7629_7629+4del		splice_donor_variant, coding_sequence_variant	51/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250372 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135384

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458648 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725506

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2023	Variant summary: ATM c.7629_7629+4delTGTAA 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 canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in exon skipping (Laake_2000). The variant allele was found at a frequency of 4e-06 in 250372 control chromosomes (gnomAD). c.7629_7629+4delTGTAA has been reported in the literature in a family affected with Ataxia-Telangiectasia with another pathogenic variant in trans (Laake_2000). The following publication has been ascertained in the context of this evaluation (PMID: 10980530). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Using RNA studies, this variant has been reported to result in an in-frame deletion of 38 amino acids in exon 53 (PMID: 10980530). However, specific data was not shown. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the canonical splice site is present in gnomAD (v2) at a frequency of 0.000004 (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 – Other splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The c.7629+1G>A and c.7629+2T>C canonical splice site variants have been classified as likely pathogenic in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 4 individuals with ataxia-telangiectasia (ClinVar, PMID: 10980530). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 232873). Disruption of this splice site has been observed in individual(s) with ataxia telangiectasia (PMID: 10980530). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs751497695, gnomAD 0.0009%). This sequence change affects a splice site in intron 51 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 10, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 13, 2024	The c.7629_7629+4delTGTAA pathogenic mutation spans the boundary of coding exon 50 and intron 50 of the ATM gene. This mutation results from a deletion of five nucleotides at positions 7629 to 7629+4. In one study, this mutation was detected and confirmed to be in trans with a second pathogenic ATM mutation in an ataxia-telangiectasia (AT) patient. mRNA analysis confirmed that this mutation causes complete skipping of coding exon 50, which is predicted to lead to the in-frame deletion of 38 amino acids at codons 2506 to 2543 (Laake K et al. Hum Mutat. 2000 Sep;16(3):232-46). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 08, 2021	This variant causes a deletion of 5 nucleotides in the exon 51 and intron 51 junction of the ATM gene. RNA extracted from carrier-derived cells have shown that the variant leads to the skipping of exon 51 (also know as exon 53 in the literature), which is expected to result in an in-frame deletion of 38 amino acids (PMID: 10980530). This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in an individual affected with ataxia telangiectasia (PMID: 10980530). This variant has been identified in 1/250372 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 Pathogenic. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 31, 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

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: rs876660041; hg19: chr11-108202280;