rs876660567

Positions:

• chr11-108354824-AC-A

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.8802del​(p.Met2935TrpfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,486 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. T2934T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.87

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108354824-AC-A is Pathogenic according to our data. Variant chr11-108354824-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233677.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.8802del	p.Met2935TrpfsTer3	frameshift_variant	61/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.8802del	p.Met2935TrpfsTer3	frameshift_variant	61/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461486 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727076

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2023	This sequence change creates a premature translational stop signal (p.Met2935Trpfs*3) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 10817650). ClinVar contains an entry for this variant (Variation ID: 233677). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 15, 2015	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 05, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 14, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with ataxia-telangiectasia (Li 2000); This variant is associated with the following publications: (PMID: 10817650) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2022

The c.8802delC pathogenic mutation, located in coding exon 60 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 8802, causing a translational frameshift with a predicted alternate stop codon (p.M2935Wfs*3). This mutation was detected in a cohort of ataxia-telangiectasia (A-T) patients (Li A et al. Am. J. Med. Genet. 2000 May;92(3):170-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660567; hg19: chr11-108225551;