rs730881294

Positions:

• chr11-108335956-TATAAG-T

Variant summary

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

The NM_000051.4(ATM):​c.8264_8268del​(p.Tyr2755CysfsTer12) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,601,372 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y2755Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• 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]

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 11-108335956-TATAAG-T is Pathogenic according to our data. Variant chr11-108335956-TATAAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 181865.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.8264_8268del	p.Tyr2755CysfsTer12	frameshift_variant, splice_region_variant	56/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.8264_8268del	p.Tyr2755CysfsTer12	frameshift_variant, splice_region_variant	56/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250752 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1449180 Hom.: 0 AF XY: 0.00000277 AC XY: 2 AN XY: 721994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000454

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74410

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 25, 2015	Variant summary: The variant is a deletion of five nucleotides spanning over the border of exon and intron 56. 5/5 in silico tools via Alamut predict this deletion to result in loss of splice donor site along with mutation taster predicting disease causing outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00084% which does not exceed the maximal expected allele frequency of a disease causing ATM allele (0.4%). It was reported in AT patients in compound heterozygosity with potentially pathogenic ATM variants and was also observed in breast cancer patients in a heterozygous form indicating the variant to be pathogenic for both AT and breast cancer. Additionally, clinical diagnostic laboratories classify variant as Pathogenic via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	This sequence change creates a premature translational stop signal (p.Tyr2755Cysfs*12) in the ATM gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs730881294, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with ataxia-telangiectasia and/or breast cancer (PMID: 1098053, 9463314, 12815592, 21445571, 21965147, 26296701, 26681312). ClinVar contains an entry for this variant (Variation ID: 181865). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ATM function (PMID: 19431188). Studies have shown that this premature translational stop signal results in skipping of exon 56, but is expected to preserve the integrity of the reading-frame (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.8264_8268delATAAG;p.(Tyr2755Cysfs*12) is a null frameshift variant (NMD) in the ATM gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 27664052) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 181865; PMID: 27664052; PMID: 30197789; PMID: 26296701) - PS4. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 02, 2017	- -
Pathogenic, criteria provided, single submitter	research	Center for Individualized Medicine, Mayo Clinic	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Sep 12, 2016	This heterozygous variant in the ATM gene (autosomal recessive transmission), inherited from the mother, was present in a female patient who also harbours a second variant in the same gene inherited by the father (compound heterozygosity). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Feb 03, 2022	The ATM c.8264_8268del (p.Tyr2755CysfsTer12) change deletes five nucleotides and causes a frameshift and the creation of a premature stop codon. A functional study has shown that this variant has no detectable kinase activity (PVS1; PMID: 19431188). This variant is predicted to result in loss of the native splice donor site, and skipping of exon 56 has been confirmed by RNA studies (PMID: 10980530; internal data). This variant has a maximum frequency of 0.0056% in gnomAD v2.1.1 ( https://gnomad.broadinstitute.org/variant/11-108206683-TATAAG-T?dataset=gnomad_r2_1 ), and is not reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). This variant has been reported in individuals with ataxia telangiectasia and breast cancer (PS4; PMID: 9463314, 10980530, 12815592, 15039971, 21445571, 21792198, 21965147, 26296701, 26681312). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2022	Predicted to result in protein truncation or nonsense mediated decay, either by frameshift or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Laake et al., 2000; Tavtigian et al., 2009); Published functional studies demonstrate a damaging effect: loss of kinase activity (Barone et al., 2009); Observed with a pathogenic ATM variant in patients with ataxia telangiectasia (Stankovic et al., 1998; Mitui et al., 2003; Demuth et al., 2011; Carranza et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 35154108, 29922827, 21792198, 9463314, 21965147, 10980530, 10330348, 15039971, 19781682, 20346647, 28779002, 12815592, 26296701, 25793145, 21445571, 28170084, 33436325, 35245693, 35264596, 27664052, 19431188) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 09, 2023	The c.8264_8268delATAAG pathogenic mutation, located in coding exon 55 of the ATM gene, results from a deletion of 5 nucleotides between nucleotide positions 8264 and 8268, causing a translational frameshift with a predicted alternate stop codon (p.Y2755Cfs*12). This alteration removes the last base pair of coding exon 55, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This alteration has been reported in a compound heterozygous state in multiple individuals with classic ataxia-telangiectasia (A-T) of different ethnic origins including the following: British/Caucasian (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62(2):334-45; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31; Barone G et al. Hum. Mutat. 2009 Aug;30(8):1222-30; Reiman A et al. Br. J. Cancer. 2011 Aug;105:586-91), Portuguese/Brazilian (Coutinho G et al. Am. J. Med. Genet. A 2004 Apr;126A(1):33-40; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82), Norwegian (Laake K et al. Hum. Mutat. 2000 Sep;16(3):232-46), and Spanish (Mitui M et al. Hum. Mutat. 2003 Jul;22(1):43-50; Graña B et al. Breast Cancer Res. Treat. 2011 Jul;128(2):573-9). As this alteration has been identified in a number of different haplotypes, some authors suggest that c.8264_8268delATAAG may be a recurring mutational event as opposed to a founder mutation. This alteration has also been reported in a cohort of women with invasive breast cancer (Ellingson MS et al. Breast Cancer Res. Treat. 2015 Sep;153:435-43) and in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). One publication suggests this alteration is associated with a 2-fold risk for developing breast cancer (Hollestelle A et al. Curr. Opin. Genet. Dev. 2010 Jun;20:268-76). Further, one study modeled this alteration to determine the stability and kinase activity of the resulting proteins and found that c.8264_8268delATAAG resulted in inactive kinase (Barone G et al. Hum. Mutat. 2009 Aug;30(8):1222-30). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 06, 2023	This variant deletes the last 5 nucleotides from exon 56 of the ATM gene. It is predicted to create a frameshift and premature translation stop signal (p.Tyr2755Cysfs*12) and to result in an absent or non-functional protein product. In addition, splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study using carrier-derived RNA has reported that the variant leads to the skipping of exon 56 (also known as exon 58 in the literature) in the RNA transcript (PMID: 10980530). The aberrant transcript is predicted to result in an in-frame deletion of 39 amino acids (p.Gly2718_Lys2756del) and to disrupt the kinase domain of the ATM protein. A functional study has shown that this variant protein has no detectable kinase activity (PMID: 19431188). This variant has been reported in many individuals affected with ataxia telangiectasia (PMID: 9463314, 10980530, 12815592, 15039971, 21792198, 21965147). This variant has also been reported in individuals affected with breast cancer (PMID: 21445571, 26296701, 26681312). This variant has been identified in 3/282098 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. -

Familial cancer of breast Pathogenic:2

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	Mar 04, 2024	- -

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: rs730881294; hg19: chr11-108206683;