rs786202800

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000051.4(ATM):c.8395_8404del(p.Phe2799LysfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,922 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ATM
NM_000051.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 3.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 11-108343337-ATTTCAGTGCC-A is Pathogenic according to our data. Variant chr11-108343337-ATTTCAGTGCC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108343337-ATTTCAGTGCC-A is described in Lovd as [Pathogenic]. Variant chr11-108343337-ATTTCAGTGCC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.8395_8404del	p.Phe2799LysfsTer4	frameshift_variant	57/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.8395_8404del	p.Phe2799LysfsTer4	frameshift_variant	57/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251232

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135770

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461712

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

727158

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 10, 2020	Variant summary: ATM c.8395_8404del10 (p.Phe2799LysfsX4) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251232 control chromosomes (gnomAD). c.8395_8404del10 has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Nahas_2009, Mitui_2003, Soukupova_2011). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated the most pronounced variant effect results in <10% of normal phosphorylation activity (Nahas_2009). Five 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 (4x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Phe2799Lysfs*4) 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 (rs761367329, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9792409, 9887333, 10817650, 12815592, 21833744, 25980754, 27978560). This variant is also known as 839del10. ClinVar contains an entry for this variant (Variation ID: 186242). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frame (c.8395_8404del) variant has been reported previously in patients affected with Ataxia-telangiectasia (Li A, Swift M., 200). The p.Phe2799LysfsTer4 variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. This variant causes a frameshift starting with codon Phenylalanine 2799, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Phe2799LysfsTer4. Loss-of-function variants in ATM are known to be pathogenic (Huang et. al., 2013). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2024	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); Also known as 8395del10; This variant is associated with the following publications: (PMID: 10817650, 35534704, 33309985, 35892882, 36243179, 37024097, 36451132, 29906526, 32980694, 34637943, 25980754, 15039971, 27978560, 21833744, 30287823, 18718650, 30322717, 31285527, 9792409, 9887333, 22649200, 26896183, 29625052, 31948886, 33919281, 33436325, 32888943, 12815592, 28767289, 38355628) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 21, 2022	PM3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ATM: PVS1, PM2 -

Familial cancer of breast

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 02, 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	Feb 27, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 21, 2022	PVS1, PM2, PM3 -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 28, 2024	The c.8395_8404del10 pathogenic mutation, located in coding exon 56 of the ATM gene, results from a deletion of 10 nucleotides at nucleotide positions 8395 to 8404, causing a translational frameshift with a predicted alternate stop codon (p.F2799Kfs*4). This mutation has been reported in cohorts of individuals with classic ataxia-telangiectasia (Broeks A et al. Hum. Mutat. 1998;12:330-7; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50) and two unrelated individuals diagnosed with sporadic pancreatic ductal adenocarcinoma at ages 35 and 55, respectively (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). Of note, this alteration is also designated as 8385del10 in published literature. 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	Sep 19, 2022	This variant deletes 10 nucleotides in exon 57 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 affected with ataxia telangiectasia (PMID: 10817650, 12815592, 21665257, 21833744). This variant has also been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 27978560) and pancreatic cancer (PMID: 28767289, 35892882). This variant has been identified in 5/251232 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	curation	Sema4, Sema4	Jan 26, 2021	- -

ATM-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

The ATM c.8395_8404del10 variant is predicted to result in a frameshift and premature protein termination (p.Phe2799Lysfs*4). This variant has been reported in multiple individuals with ataxia telangiectasia (Huang et al. 2018. PubMed ID: 29625052; Momozawa et al. 2018. PubMed ID: 30287823; Carter et al. 2018. PubMed ID: 30322717; Hutchings et al. 2019. PubMed ID: 31285527). This variant has also been reported in individuals with pancreatic cancer and colon cancer (Shindo et al. 2017. PubMed ID: 28767289; Yurgelun et al. 2015. PubMed ID: 25980754; Pearlman et al. 2017. PubMed ID: 27978560). Functional studies have shown this variant results in less than 10% of normal phosphorylation activity (Nahas et al. 2009. PubMed ID: 19147735). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186242/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Breast carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 20, 2021

Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

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