rs587781978

Positions:

• chr11-108244912-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM3_Strong PM5_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.790delT (p.Y264Ifs*12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001763 (2/113450 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 4 individuals with Ataxia-Telangiectasia (PMID:12815592, 9887333, 26896183, 22213089). In summary, this variant meets the criteria to be classified as a pathogenic variant for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM3_strong, PM5_supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA166283/MONDO:0016419/020

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 7.43

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: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.790del	p.Tyr264IlefsTer12	frameshift_variant	7/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.790del	p.Tyr264IlefsTer12	frameshift_variant	7/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251032 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135678

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461418 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727028

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change creates a premature translational stop signal (p.Tyr264Ilefs*12) 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 present in population databases (rs774609577, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9887333, 12673797, 12815592, 15928302, 16832357, 22213089, 24549055). ClinVar contains an entry for this variant (Variation ID: 141742). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2017	Variant summary: The ATM c.790delT (p.Tyr264Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.1027_1030delGAAA [p.Glu343fs). One in silico tool predicts a damaging outcome for this variant. The variant has been identified in numerous patients affected with ataxia telangiectasia and/or breast cancer and has not been observed in healthy individuals (e.g., Renwick_2006; Buzin_2003; Castera_2014). In addition, a functional study revealed that a patient carrying the variant of interest and a second truncating ATM variant (c.1563_1564delAG [p.Glu522fs]) had no detectable ATM expression or kinase activity (Verhagen_HM_2012), suggesting the variant is a functional null allele. This variant is absent in the large control database ExAC (0/122508 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 05, 2016	- -

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Jan 25, 2024	The c.790delT (p.Y264Ifs*12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001763 (2/113450 alleles) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 4 individuals with Ataxia-Telangiectasia (PMID: 12815592, 9887333, 26896183, 22213089). In summary, this variant meets the criteria to be classified as a pathogenic variant for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM3_strong, PM5_supporting) -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 11, 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	MGZ Medical Genetics Center	Jul 11, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 07, 2021	This variant deletes 1 nucleotide in exon 7 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 9887333, 10817650, 12552559, 12815592, 15928302, 16411093, 21665257, 22213089, 25122203). This variant has also been reported in individuals affected with breast, ovarian, colorectal and prostate cancer (PMID: 16832357, 19781682, 20346647, 24549055, 27433846, 27616075, 28135145, 28779002). This variant has been identified in 2/251032 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.	Dec 05, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2021	The c.790delT pathogenic mutation, located in coding exon 6 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 790, causing a translational frameshift with a predicted alternate stop codon (p.Y264Ifs*12). This alteration has been reported in conjunction with a second pathogenic mutation in multiple individuals with ataxia-telangiectasia (A-T) (Sandoval N et al. Hum Mol. Genet. 1999 Jan;8(1):69-79; Mitui M et al. Hum. Mutat. 2003 Jul;22(1):43-50; Buzin C et al. Hum. Mutat. 2003 Feb;21(2):123-31; Heinrich T et al. Eur. J. Pediatr. 2006 Apr;165(4):250-7; Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71). This alteration has also been identified in individuals diagnosed with prostate cancer, breast cancer and colorectal cancer (Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53; Decker B et al. J. Med. Genet., 2017 Nov;54:732-741; Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102; Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095). 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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with personal and/or family history of ATM-related cancers (Renwick et al., 2006; Castera et al., 2014; Pritchard et al., 2016; Decker et al., 2017); This variant is associated with the following publications: (PMID: 16832357, 16411093, 29625052, 32853339, 26896183, 32818697, 35154108, 29922827, 35047863, 29478780, 9887333, 22213089, 12673797, 15928302, 12552559, 10817650, 20346647, 27616075, 27433846, 23566627, 28152038, 24549055, 28779002, 26689913, 31731261, 12815592) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -

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: rs587781978; hg19: chr11-108115639;