rs786203370

Positions:

• chr11-108227838-GCATT-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.138_141del​(p.His46GlnfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000342 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.88

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: 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 11-108227838-GCATT-G is Pathogenic according to our data. Variant chr11-108227838-GCATT-G is described in ClinVar as [Pathogenic]. Clinvar id is 186975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.138_141del	p.His46GlnfsTer9	frameshift_variant	3/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.138_141del	p.His46GlnfsTer9	frameshift_variant	3/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461262 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726902

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change creates a premature translational stop signal (p.His46Glnfs*9) 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 ataxia-telangiectasia (PMID: 9463314, 22071889). This variant is also known as c.138_141del4 and 136del4nt. ClinVar contains an entry for this variant (Variation ID: 186975). For these reasons, this variant has been classified as Pathogenic. -

ATM-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2023

The ATM c.138_141delTTCA variant is predicted to result in a frameshift and premature protein termination (p.His46Glnfs*9). This variant along with a second variant in this gene was reported in two individuals with ataxia telangiectasia, who also have personal history of T-cell lymphoma (reported as 136del4nt in Table 1 and Table 4, Stankovic et al 1998. PubMed ID: 9463314; Jacquemin et al. 2011. PubMed ID: 22071889). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in ATM are expected to be pathogenic. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/186975/). This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2018

This deletion of four nucleotides in ATM is denoted c.138_141delTTCA at the cDNA level and p.His46GlnfsX9 (H46QfsX9) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GGCA[delTTCA]GATT. The deletion causes a frameshift which changes a Histidine to a Glutamine at codon 46, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.138_141delTTCA, also reported as ATM 136del4 using alternate nomenclature, has been reported with a second ATM variant in two siblings and at least one other individual with Ataxia-telangiectasia (Stankovic 1998, Jacquemin 2012). Functional studies on cell lines derived from these individuals found decreased ATM protein levels, impaired phosphorylation after exposure to ionizing radiation, and absent kinase activity (Stewart 2001, Jacquemin 2012). Based on current evidence, we consider this variant to be pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 05, 2024

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2022

The c.138_141delTTCA pathogenic mutation, located in coding exon 2 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 138 to 141, causing a translational frameshift with a predicted alternate stop codon (p.H46Qfs*9). 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: rs786203370; hg19: chr11-108098565;