11-108335959-A-T

Position:

• chr11-108335959-A-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.8266A>T (p.Lys2756*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in 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 been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID:10330348, 12552559, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003887 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting, PM3_Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA293899/MONDO:0700270/020

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (1 hom.)
• Consequence: ATM NM_000051.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9626
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 8.80

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 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.8266A>T	p.Lys2756*	stop_gained, splice_region_variant	56/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8266A>T	p.Lys2756*	stop_gained, splice_region_variant	56/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 32

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: 0.0000160 AC: 4 AN: 250702 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135496

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: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000489 AC: 71 AN: 1451428 Hom.: 1 Cov.: 27 AF XY: 0.0000456 AC XY: 33 AN XY: 722974

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000617

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

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

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2016	Variant summary: The ATM c.8266A>T (p.Lys2756X) 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.8264_8268delATAAG/p.Tyr2755fsX12). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/118602 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant has been reported in multiple patients with AT and different types of cancers. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Lys2756*) 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 (rs371638537, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T), chronic lymphocytic leukemia, medulloblastoma, pancreatic cancer, breast cancer and prostate cancer (PMID: 8659541, 9463314, 10330348, 11756185, 12552559, 21933854, 22585167, 25503501, 26094658, 26681312, 28007021). 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: 135780). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a deleterious intronic mutation in a 7-month-old female with immune deficiency, hearing loss, and skin lesion. -

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 01, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, 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) and susceptibility to breast cancer (MIM#114480). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic variants in this gene result in ataxia-telangiectasia; however, heterozygous carriers of specific pathogenic variants have an increased risk of breast cancer (PMID: 27595995). Germline variants in this gene may also contribute to increased risk of other cancers including gastric, colorectal, and pancreatic cancers, however the risk is not well-established at this stage (PMIDs: 22585167, 27978560, 26506520). (I) 0115 - Variants in this gene are known to have variable expressivity with regard to ataxia-telangiectasia. 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 (v4: 71 heterozygotes, 1 homozygote). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic by clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 04, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2022	The p.K2756* pathogenic mutation (also known as c.8266A>T), located in coding exon 55 of the ATM gene, results from an A to T substitution at nucleotide position 8266. This changes the amino acid from a lysine to a stop codon within coding exon 55. This mutation has been reported in multiple individuals diagnosed with ataxia-telangiectasia (A-T) (Telatar M et al. Am. J. Hum. Genet. 1996 Jul;59:40-4; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31). This alteration has also been detected in individuals with personal and/or family histories of breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8; Aloraifi F et al. FEBS J. 2015 Sep;282:3424-37; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). 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	Feb 27, 2023	This variant changes 1 nucleotide in exon 56 of the ATM gene, creating a 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: 8659541, 9463314, 10330348, 12552559, 21665257). This variant has also been reported in individuals affected with breast cancer (PMID: 20305132, 25503501, 26094658, 26534844. 26681312, 28008555) and pancreatic cancer (PMID: 22585167). This variant has been identified in 5/282078 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.	Nov 28, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 13, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ATM: PVS1, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 09, 2015	NMD is expected as a result of this variant, and therefore the loss of a functional protein. Additionally, the variant was found in at least one symptomatic patient, and found in general population data at a frequency that is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2022	Nonsense 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); Observed in the heterozygous state in individuals with ATM-related cancers (Yuille 2002, Buzin 2003, Skowronska 2012, Roberts 2012, Desmond 2015, Maxwell 2015, Schrader 2016, Decker 2017, Pritzlaff 2017); This variant is associated with the following publications: (PMID: 25525159, 10330348, 9463314, 25503501, 22585167, 26681312, 26556299, 28008555, 27159321, 26094658, 28779002, 30549301, 29922827, 28888541, 12091354, 8659541, 21933854, 24486587, 24763289, 12552559, 25032865, 18321536, 26270727, 21459046, 16953663, 28007021, 26786923, 27324988, 28716242, 28729543, 11756185, 9872980, 25326635, 30716324, 30620386, 30322717, 30113427, 31447099, 26896183, 32853339, 32885271, 31948886, 31285527) -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 12, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

ATM-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2024

The ATM c.8266A>T variant is predicted to result in premature protein termination (p.Lys2756*). This variant has been reported to be causative for ataxia telangiectasia, chronic lymphocytic leukemia, and breast and pancreatic cancer (Table 1, Telatar et al. 1996. PubMed ID: 8659541; Skowronska. et al. 2012. PubMed ID: 21933854; Roberts et al. 2012. PubMed ID: 22585167; Aloraifi et al. 2015. PubMed ID: 26094658). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as pathogenic by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135780/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Lys2756* variant was identified in 9 of 23570 proband chromosomes (frequency: 0.0004) from individuals or families with breast or pancreatic cancer or ataxia-telangiectasia and was not identified in 582 control chromosomes from healthy individuals (Aloraifi 2015, Susswein 2015, Maxwell 2014, Desmond 2015, Buzin 2003, Roberts 2012, Stankovic 1998, Telatar 1996). In one of these studies, the variant was found to segregate with disease in the affected pancreatic kindred and tumour analysis showed loss of wildtype allele (Roberts 2012).The variant was also identified in dbSNP (ID: rs371638537 as “With Pathogenic, Uncertain significance allele”), ClinVar (classified pathogenic by Invitae, Ambry Genetics, GeneDx, Color Genomics and Integrated Genetics/Laboratory Corporation of America and as likely pathogenic by Counsyl), Cosmic (in a lymphoid neoplasm/CLL), and LOVD 3.0 (1x). The variant was not identified in GeneInsight-COGR or MutDB databases. The variant was identified in control databases in 5 of 276440 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), specifically in the European Non-Finnish population in 5 of 126164 chromosomes (freq: 0.00004) and was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The variant was found to co-occur with several pathogenic variants: CHEK2 c.1100delC p.Thr367Metfs*15; CHEK2 c.1263delT p.Ser422Valfs*15; and CHEK2 c.444+1G>A in 3 breast cancer patients and ATM c.2250G>A, c.2125del126; and ATM c.1058_1059delGT in 2 ataxia-telangiectasia patients (Teraoka 1999, Skowronska 2012, Susswein 2015, Maxwell 2014). The ATM c.8266A>T variant also occurs in the last three bases of exon 56. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Further, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing. The p.Lys2756* variant is predicted to create a premature stop codon at position 2756, which is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.97
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.030		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: rs371638537; hg19: chr11-108206686; COSMIC: COSV53745400; COSMIC: COSV53745400;