rs587780624

Positions:

• chr11-108235814-TATCTC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000051.4(ATM):​c.478_482del​(p.Ser160AlafsTer23) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000616 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 3.61

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-108235814-TATCTC-T is Pathogenic according to our data. Variant chr11-108235814-TATCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185501.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.478_482del	p.Ser160AlafsTer23	frameshift_variant	5/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.478_482del	p.Ser160AlafsTer23	frameshift_variant	5/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251342 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135846

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461534 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727088

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change creates a premature translational stop signal (p.Ser160Alafs*23) 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 breast and/or ovarian cancer (PMID: 26270727). ClinVar contains an entry for this variant (Variation ID: 185501). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 01, 2023	Variant summary: ATM c.478_482delTCTCA (p.Ser160AlafsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251342 control chromosomes. c.478_482delTCTCA has been reported in the literature as a presumably compound heterozygous genotype in at-least one individual with Ataxia-Telangiectasia and as a carrier genotype in an individual with breast cancer (example, Izatt_1999, Desmond_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Nov 03, 2023	The following ACMG criteria is used: PVS1, PM2_Supporting (not reported in gnomAD), PM3_Supporting (detected in trans with a pathogenic variant). -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATM: PVS1, PM2, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 26, 2019	DNA sequence analysis of the ATM gene demonstrated a five base pair deletion in exon 5, c.478_482del. This likely pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 22 amino acids downstream of the mutation, p.Ser160Alafs*23. This likely pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. The p.Ser160Alafs23* change has been identified in a patient referred for genetic testing for hereditary breast and/or ovarian cancer (PMID: 26270727). The p.Ser160Alafs*23 change is reported in the gnomAD database in the heterozygous state in a single individual (dbSNP rs587780624). Truncating variants in the ATM gene have been observed in patients with breast cancer and in patients with ataxia. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2023	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 26270727); Reported in the compound heterozygous state in a child with ataxia-telangiectasia (PMID: 30420857); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21933854, 10234507, 23726790, 31360874, 37715651, 31447099, 30420857, 26270727) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 01, 2021	The c.478_482delTCTCA pathogenic mutation, located in coding exon 4 of the ATM gene, results from a deletion of 5 nucleotides at nucleotide positions 478 to 482, causing a translational frameshift with a predicted alternate stop codon (p.S160Afs*23). This alteration was reported in an individual with ataxia telangiectasia (A-T). The second ATM alteration was not identified for this patient, but protein analysis showed severely reduced protein levels (Izatt L et al. Eur. J. Hum. Genet. 1999 Apr;7:310-20). This alteration has also been reported in another individual with A-T, identified in the compound heterozygous state with a second ATM alteration (Bakhtiar S et al. Front Immunol, 2018 Oct;9:2495). This variant was reported in 4/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2020	This variant deletes 5 nucleotides in exon 5 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals suspected of hereditary breast or ovarian cancer and an individual with ataxia-telangiectasia in the literature (PMID: 10234507, 26270727). This variant has been identified in 1/251342 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 11, 2022	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 10, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

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: rs587780624; hg19: chr11-108106541;