11-108343371-GGTGA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_000051.4(ATM):​c.8418+5_8418+8delGTGA variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 9.65
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
PP5
Variant 11-108343371-GGTGA-G is Pathogenic according to our data. Variant chr11-108343371-GGTGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATMNM_000051.4 linkuse as main transcriptc.8418+5_8418+8delGTGA splice_region_variant, intron_variant ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.8418+5_8418+8delGTGA splice_region_variant, intron_variant NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152068
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00000398
AC:
1
AN:
251020
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135658
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000493
AC:
72
AN:
1461530
Hom.:
0
AF XY:
0.0000440
AC XY:
32
AN XY:
727062
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000648
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152068
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74268
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Pathogenic:5
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 02, 2024This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8845835, 10817650, 12552559, 21792198]. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJun 11, 2018- -
Pathogenic, no assertion criteria providedresearchKing Laboratory, University of WashingtonSep 01, 2019- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 07, 2024- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with ataxia-telangiectasia (MIM#208900), and cancer susceptibility (MIM#114480) (OMIM). Missense variants have been shown to interfere with endogenous ATM protein activity (PMID: 20301790, PMID: 19431188). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic variants in this gene result in ataxia-telangiectasia, whereas heterozygous individuals have a greater susceptilbity to different forms of cancer (OMIM). (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 (PMID: 20301790, PMID: 27884168). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown by RT-PCR to cause exon 57 skipping resulting in the inframe loss of 50 amino acids (p.(Val2757_Met2806del)) (PMID: 8845835, PMID: 31843900). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a condition (3 heterozygotes, 0 homozygotes). (SP) 0601 - Variant results in the partial loss of the well-established PI3K/PI4K domain, including multiple ATP binding sites (NCBI, UniProt). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and described in a compound heterozygous state in multiple individuals with ataxia-telangiectasia with or without cancer, and a heterozygous state in individuals with breast or prostate cancer (ClinVar, PMID: 27433846, PMID: 8845835, PMID: 31843900, PMID: 28008555). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Ataxia-telangiectasia syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 28, 2020Variant summary: ATM c.8418+5_8418+8delGTGA alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. One predict the variant weakens a 5' donor site. Experimental studies have shown the variant to result in exon skipping (Wright_1996). The variant allele was found at a frequency of 4e-06 in 251020 control chromosomes. c.8418+5_8418+8delGTGA has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia in the compound heterozygous state (Buzin_2003, Hacia_1998, Li_2000, Pritzlaff_2017) as well as breast and prostate cancers in the heterozygous state (Pritchard_2016, Susswein_2016). Eight 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024This sequence change falls in intron 57 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs769139997, gnomAD 0.002%). This variant has been observed in individuals with ATM-related conditions (PMID: 9872980, 10817650, 12552559, 26681312, 27433846). This variant is also known as c.8269delta150, 8418+1delGTGA, IVS59+1del4, and IVS59+5_IVS59+8delGTGA. ClinVar contains an entry for this variant (Variation ID: 181866). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 57 (also known as exon 59), but is expected to preserve the integrity of the reading-frame (PMID: 8808599; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaApr 05, 2016- -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 27, 2018The frequency of this variant in the general population, 0.000016 (2/128848 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32885271 (2021), 26681312 (2015), 19781682 (2009)), prostate cancer (PMID: 33436325 (2021), 32853339 (2021), 32338768 (2020)), and ataxia-telangiectasia (PMID: 9463314 (1998), 9872980 (1998), 30549301 (2019), 28008555 (2017)). This variant has also been shown to result in exon 59 skipping (PMID: 8808599 (1996)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper ATM mRNA splicing. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 31, 2024Non-canonical splice site variant demonstrated to result in an in-frame deletion of a critical region (PMID: 31843900, 8808599); Observed in the heterozygous state in individuals with prostate, breast, or pancreatic cancer (PMID: 27433846, 32338768, 32853339, 33436325, 35047863); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9872980, 31447099, 30549301, 9463314, 10817650, 28008555, 12552566, 12552559, 26681312, 8808599, 23532176, 31843900, 33436325, 32338768, 32885271, 32866655, 32853339, 35047863, 29922827, 35078243, 27433846, 8845835) -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsMar 07, 2024The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) In multiple individuals with ataxia-telangiectasia, this variant has been seen with a single recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal RNA splicing (PMID: 8808599). Though the reading frame is expected to be maintained, it disrupts an important region of the protein, and therefore, is expected to disrupt its function. -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 19, 2020DNA sequence analysis of the ATM gene demonstrated a sequence change close to the splice donor site of intron 57, c.8418+5_8418+8del. This sequencing change has been described in the gnomAD database with a low population frequency of 0.0007% (dbSNP rs1060499575). This sequence change has been previously reported in the compound heterozygous state in individuals with ataxia-telangiectasia (PMIDs: 30549301, 9872980, 10817650, 12552559, 28008555). It has also been reported in breast and prostate cancer patients (PMIDs: 26681312, 27433846). Functional study shows the c.8418+5_8418+8del variant causes a skipping of exon 57, and results in a short mRNA transcript with 150-base pair deletion (PMID: 8808599). Collectively these evidences indicate that, the c.8418+5_8418+8del sequence is pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 16, 2021This variant deletes 4 nucleotides at the +5 to +8 position of intron 57 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant causes the skipping of exon 57 (PMID: 8845835, 31843900), resulting in an in-frame deletion of 50 amino acids within the kinase domain of the ATM protein. Although protein functional studies have not been reported, this variant is expected to disrupt the kinase activity of the ATM protein. This variant (also known as c.8418+1_8418+4del, IVS59+1del4, IVS59+5_IVS59+8del and 8269del150 in the literature) has been reported in individuals affected with breast cancer (PMID: 16832357, 19781682, 26681312, 28008555) and prostate cancer (PMID: 27433846). This variant has also been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 8808599, 8845835, 9463314, 9872980, 10817650, 12552559, 28008555). This variant has been identified in 2/282394 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 submitterclinical testingAmbry GeneticsJul 26, 2022The c.8418+5_8418+8delGTGA intronic pathogenic mutation (also known as c.8418+1_8418+4delGTGA) is located 5 nucleotides after coding exon 56 of the ATM gene. This mutation results from a deletion of 4 nucleotides at positions c.8418+5 to c.8418+8 which affects the splice donor site and was reported to result in the deletion of coding exon 56 (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59(4):839-46). RNA studies have shown skipping of coding exon 56 in samples with this alteration (Ambry internal data). This mutation has been reported as compound heterozygous in numerous patients with ataxia-telangiectasia (AT) (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59(4):839-46; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62(2):334-45; Li A and Swift M. Am. J. Med. Genet. 2000 May;92(3):170-7; Buzin CH et al. Hum. Mutat. 2003 Feb;21(2):123-31). This mutation has also been reported in individuals with male breast cancer (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586), metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53), and breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Based on available evidence, this alteration is interpreted as a disease-causing mutation. -
Carcinoma of colon Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The ATM c.8418+5_8418+8del variant was identified in 8 of 23168 proband chromosomes (frequency: 0.0003) from individuals or families with Ataxia-Telangiectasia (AT), breast cancer or prostate cancer (Buzin 2003, Li 2000, Pritchard 2016, Pritzaff 2016, Susswein 2015), including 1 homozygote affected with AT (Li 2000). The variant was also identified in dbSNP (ID: rs730881295) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, and two other submitters). The variant was not identified in LOVD 3.0. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.8418+5_8418+8del variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant is classified as pathogenic. -
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioFeb 08, 2023- -
Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineAug 17, 2018This c.8418+5_8418+8delGTGA variant in the ATM gene was experimentally demonstrated to cause exon skipping and result in a shortened mRNA transcript (PMID: 8808599). This variant has been reported in several individuals affected with ataxia-telangiectasia (MIM # 208900, PMID: 9872980, 10817650, 12552559) and in a patient affected with prostate cancer (PMID: 27433846). This variant has an extremely low frequency in large databases of genetic variation in the general population. Therefore, this c.8418+5_8418+8delGTGA variant in the ATM gene is classified as pathogenic. -
ATM-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 27, 2024The ATM c.8418+5_8418+8delGTGA variant is predicted to result in an intronic deletion. This variant has been reported many times in the literature using different naming conventions, including: IVS57+5_IVS57+8delGTGA, IVS59+5_IVS59+8delGTGA, IVS59+1del4, 8418+1delGTGA, and 8269del150. It has been detected in the compound heterozygous state in several individuals with ataxia telangiectasia (Hacia et al. 1998. PubMed ID: 9872980; Li and Swift. 2000. PubMed ID: 10817650; Buzin et al. 2003. PubMed ID: 12552559; Pritzlaff et al. 2017. PubMed ID: 28008555) and in the heterozygous state in at least one individual with breast cancer (Susswein et al. 2016. PubMed ID: 26681312) and one individual with prostate cancer (Pritchard et al. 2016. PubMed ID: 27433846). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181866/). Multiple in silico splicing prediction tools indicate that the variant dramatically weakens the nearby donor site (Alamut Visual v2.11), and RNA studies indicate that it causes exon skipping (Wright et al. 1996. PubMed ID: 8808599). Taken together, we interpret this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.89
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.23
Position offset: 23
DS_DL_spliceai
0.89
Position offset: 0

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.

Other links and lift over

dbSNP: rs730881295; hg19: chr11-108214098; API