rs786203976

Positions:

chr11-108345896-ACTT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_000051.4(ATM):c.8578_8580delTCT(p.Ser2860del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ATM
NM_000051.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 8.00

Variant links:

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]

ATM links:

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]

C11orf65 links:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000051.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 11-108345896-ACTT-A is Pathogenic according to our data. Variant chr11-108345896-ACTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 3018.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.8578_8580delTCT	p.Ser2860del	conservative_inframe_deletion	58/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.8578_8580delTCT	p.Ser2860del	conservative_inframe_deletion	58/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251054

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461408

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

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

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 08, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 16, 2022	The ATM c.8578_8580delTCT (p.S2860del) variant has been observed in the compound heterozygous state (presumed) in two individuals affected with ataxia-telangiectasia and it has also been observed in the compound heterozygous state (confirmed) in an individual affected with generalized dystonia, without classical AT features (PMIDs: 22213089, 31920950 PM3_verystrong). This variant is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In silico structural impact predictors (Provean, -11.099) predict that this alteration is deleterious (PP3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 02, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19535770, 22213089, 21792198, 9792409]. -

Ataxia-telangiectasia syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This variant, c.8578_8580del, results in the deletion of 1 amino acid(s) of the ATM protein (p.Ser2860del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs786203976, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 7792600, 9792409, 19535770, 21792198, 22213089, 25572163). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3018). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 23, 1995	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 03, 2022	This variant causes an in-frame deletion of one amino acid in the kinase domain of the ATM protein. This variant has been reported in individuals affected with ataxia telangiectasia, including in the compound heterozygous state with an additional pathogenic ATM variant (PMID: 7792600, 8845835, 9259193, 9792409, 19535770, 21792198, 22213089). Cells derived from two of these individuals have shown the presence of ATM protein but no detectable ATM kinase activity (PMID: 21792198, 22213089). This variant has also been reported in the compound heterozygous state in an individual affected with dystonia (PMID: 25572163, 31920950) and in the heterozygous state in an individual affected with pancreatic cancer (PMID: 33127389). This variant has been identified in 1/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 2024	The c.8578_8580delTCT variant is located in coding exon 57 of the ATM gene. This variant results from an in-frame TCT deletion at nucleotide positions 8578 to 8580, causing the removal of a highly-conserved serine residue at codon 2860. This variant has been detected in trans with a second ATM pathogenic variant in a patient with generalized dystonia (Kuhm C et al. J Neurol, 2015 Mar;262:768-70). In addition, this variant has been observed in two unrelated patients with ataxia-telangiectasia (A-T), each harboring a second ATM pathogenic variant (Verhagen MM et al. Neurology, 2009 Aug;73(6):430-7; Verhagen MM et al. Hum Mutat, 2012 Mar;33:561-71). Functional studies have revealed low expression of ATM protein in A-T patient cell lines, without detectable kinase activity (Reiman A et al. Br J Cancer, 2011 Aug;105:586-91; Verhagen MM et al. Hum Mutat, 2012 Mar;33:561-71). Based on internal structural analysis, S2860del is predicted to disrupt the ATM kinase domain to a higher degree than nearby pathogenic variants in the same domain (Bareti D et al. Sci Adv, 2017 May;3(5):e1700933). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2024

Observed multiple times with a pathogenic ATM variant in patients with dystonia or classic ataxia telangiectasia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) alleles in some cases (PMID: 19535770, 21792198, 22213089, 25572163, 28126470, 31920950); Identified in the heterozygous state in individuals with pancreatic cancer (PMID: 33127389); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31920950, 19535770, 28194276, 28126470, 30504431, 28779002, 22213089, 21792198, 25572163, 34771661, 7792600, 15279808, 23532176, 33127389) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over