rs1450394308

Positions:

• chr11-108332850-CTTATA-C

Variant summary

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

The NM_000051.4(ATM):​c.7886_7890delTATTA​(p.Ile2629fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,882 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: 0.0000089 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 8.18

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]

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]

ATM (HGNC:):

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 11-108332850-CTTATA-C is Pathogenic according to our data. Variant chr11-108332850-CTTATA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108332850-CTTATA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.7886_7890delTATTA	p.Ile2629fs	frameshift_variant	53/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7886_7890delTATTA	p.Ile2629fs	frameshift_variant	53/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250834 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135584

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460882 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 726768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 04, 2022	Variant summary: ATM c.7886_7890delTATTA (p.Ile2629SerfsX25) 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 4e-06 in 250834 control chromosomes (gnomAD). This variant has been reported in several A-T patients/families across multiple countries in homozygous state as well as in compound heterozygous state with other pathogenic/likely pathogenic variants (Gilad_1996, Telatar_1996, Sasaki_1998, Stankovic_1998, Exley_2011, Mitui_2003, Jeddane_2013, Charlesworth_2013). Cosegregation of this variant with disease have also been reported from a family (Charlesworth_2013). It has also been found in a breast cancer patient (Hirotsu_2015), which is consistent with the fact that pathogenic variants in ATM gene are known to confer elevated risk of breast cancer in a heterozygous state. In a compound heterozygous patient that carried this variant and 3802delG, no ATM kinase activity and ATM protein expression was observed in lymphoblastoid cell line derived from the patient, strongly supporting its predicted outcome (Exley_2011). These data indicate that the variant is likely to be associated with disease. Eleven ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic (n=1) and pathogenic (n=10). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 19, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1998	- -
Pathogenic, no assertion criteria provided	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jun 19, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. Carriers of ATM pathogenic variants are at increased risk of developing cancer (mainly breast cancer) (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygotes and compound heterozygotes individuals with ataxia-telangiectasia, and in association with cancer (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Ile2629Serfs*25) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with ataxia-telangiectasia and breast cancer and/or ovarian cancer (PMID: 8845835, 9600235, 12815592, 21787400, 23322442, 23946315, 26436112). This variant is also known as 7883del5, 7884_7888del5, c.7878_7882delTTATA and c.7886_7890del. ClinVar contains an entry for this variant (Variation ID: 230200). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2021	The c.7886_7890delTATTA pathogenic mutation, located in coding exon 52 of the ATM gene, results from a deletion of 5 nucleotides at nucleotide positions 7886 to 7890, causing a translational frameshift with a predicted alternate stop codon (p.I2629Sfs*25). This pathogenic mutation has been reported in a family with two cases of breast cancer under age 50 and one individual with ataxia-telangiectasia (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73). This mutation has also been reported in a compound heterozygous state with another alteration in ATM [c.6154G>A (p.E2052K)] in an individual with cervical dopa-responsive dystonia (DRD) (Charlesworth G et al. Neurology. 2013 Sep;81:1148-51). This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration was also observed with an allele frequency of 0.00071 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry. In addition, it was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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	curation	Sema4, Sema4	Jun 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 06, 2023	This variant deletes 5 nucleotides in exon 53 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 (also known as 7883del5, 7884_7888del5, or c.7878_7882delTTATA in the literature) has been reported in the homozygous or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 8845835, 9600235, 12815592, 23322442, 23946315). This variant has also been reported in individuals affected with breast cancer (PMID: 21787400, 26436112, 30287823, 33471991) or pancreatic ductal adenocarcinoma (PMID: 34506673). This variant has been identified in 1/250834 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Goldgar 2011, Hirotsu 2015, Momozawa 2018, Kaneyasu 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.7883del5, c.7884_7888del5, c.7886_7889del5, and c.7878_7882del; This variant is associated with the following publications: (PMID: 8845835, 21459046, 21787400, 23946315, 9463314, 20346647, 9711876, 26436112, 9443866, 34489640, 29360550, 30287823, 32566746, 34262154, 9600235, 23322442, 12815592) -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 01, 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 22, 2024	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1+PM3 -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

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: rs1450394308; hg19: chr11-108203577;