rs730881295

chr11-108343371-GGTGA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PP3_Moderate PP5_Very_Strong

The NM_000051.4(ATM):c.8418+5_8418+8del variant causes a splice donor, splice donor 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_donor, splice_donor_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 9.65

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.016246865 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.1, offset of 19, new splice context is: aagGTtatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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	UniProt
ATM	NM_000051.4	c.8418+5_8418+8del		splice_donor_variant, splice_donor_region_variant, intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.8418+5_8418+8del		splice_donor_variant, splice_donor_region_variant, intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152068 Hom.: 0 Cov.: 32

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

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

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

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:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Apr 05, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2020	Variant 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 submitter	clinical testing	Invitae	Jan 15, 2024	This 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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 27, 2018	The 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 submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 19, 2020	DNA 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2018	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to negatively affect a known splice site. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2023	Observed in the heterozygous state in individuals with prostate, breast, or pancreatic cancer in the published literature (Pritchard et al., 2016; Nguyen-Dumont et al., 2020; Darst et al., 2021; Karlsson et al., 2021; Lerner-Ellis et al., 2021; Yu et al., 2022); Non-canonical splice site variant predicted to result in an in-frame deletion of a critical region (Gilad et al., 1996); 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, 8845835, 23532176, 31843900, 33436325, 32338768, 32885271, 32866655, 32853339, 27433846, 35047863, 29922827) -

Familial cancer of breast Pathogenic:4

Pathogenic, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 02, 2024	This 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]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 16, 2021	This 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 submitter	clinical testing	Ambry Genetics	Jul 26, 2022	The 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 provided

clinical testing

Department 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 submitter

clinical testing

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

Feb 08, 2023

- -

Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Aug 17, 2018

This 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. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs730881295; hg19: chr11-108214098;