Submissions for variant NM_000051.4(ATM):c.8264_8268del (p.Tyr2755fs)

gnomAD frequency: 0.00003  dbSNP: rs730881294

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159623	SCV000209609	pathogenic	not provided	2022-12-19	criteria provided, single submitter	clinical testing	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)
Center for Individualized Medicine, Mayo Clinic	RCV000190640	SCV000245683	pathogenic	Ataxia-telangiectasia syndrome	2014-01-01	criteria provided, single submitter	research
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000190640	SCV000268516	pathogenic	Ataxia-telangiectasia syndrome	2016-09-12	criteria provided, single submitter	clinical testing	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).
Ambry Genetics	RCV000221664	SCV000274579	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000190640	SCV000283075	pathogenic	Ataxia-telangiectasia syndrome	2025-01-16	criteria provided, single submitter	clinical testing	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 gene product 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 (internal data). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000221664	SCV000682470	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000190640	SCV000694374	pathogenic	Ataxia-telangiectasia syndrome	2015-11-25	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000190640	SCV000793072	pathogenic	Ataxia-telangiectasia syndrome	2017-08-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000190640	SCV000838611	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159623	SCV001446464	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
DASA	RCV000190640	SCV002107083	pathogenic	Ataxia-telangiectasia syndrome	2022-03-05	criteria provided, single submitter	clinical testing	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000190640	SCV002525963	pathogenic	Ataxia-telangiectasia syndrome	2022-02-03	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003467216	SCV004210082	pathogenic	Familial cancer of breast	2024-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467216	SCV004931198	pathogenic	Familial cancer of breast	2024-02-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159623	SCV005623214	pathogenic	not provided	2024-03-19	criteria provided, single submitter	clinical testing	The ATM c.8264_8268del (p.Tyr2755Cysfs*12) variant alters the translational reading frame of the ATM mRNA and causes the premature termination of ATM protein synthesis. Additionally, this variant removes the last 5 nucleotides of exon 56 (also known as exon 58) and experimental studies have shown it causes skipping of the affected exon, resulting in a near complete loss of kinase activity in the variant protein (PMID: 10980530 (2000), 19431188 (2009)). This variant has been reported in the compound heterozygous state in multiple individuals affected with classic ataxia-telangiectasia (A-T) (PMID: 10330348 (1999), 10980530 (2000), 15039971 (2004), 21792198 (2011), 21965147 (2011), 27664052 (2017), 28170084 (2017), 35154108 (2022)). It has also been reported in individuals affected with breast cancer (PMID: 19781682 (2009), 21445571 (2011), 26296701 (2015), 26681312 (2015), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/ATM), 35245693 (2022), 35264596 (2022)), pancreatic cancer (PMID: 29922827 (2018)), and prostate cancer (PMID: 33436325 (2021)). The frequency of this variant in the general population, 0.000011 (3/282098 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004739491	SCV005900544	pathogenic	ATM-related disorder	2024-03-09	criteria provided, single submitter	clinical testing	This frameshifting variant in exon 56 of 63 is predicted to affect normal splicing and result in loss of normal protein function; however, to our knowledge, no RNA-based splicing analysis has been performed to clarify the effect of this alteration on splicing. Loss-of-function variation in ATM is an established mechanism of disease (PMID: 20301790). This variant has been previously reported as a compound heterozygous and homozygous change in patients with ataxia-telangiectasia (PMID: 9463314, 10980530, 12815592, 15039971, 21792198, 21965147). This variant has also been reported as a heterozygous change in individuals with breast cancer (PMID: 21445571, 26296701, 26681312). Functional studies indicate this variant causes loss of ATM kinase activity (PMID: 19431188). The c.8264_8268del (p.Tyr2755CysfsTer12) variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.0007% (11/1601372) and thus is presumed to be rare. Based on the available evidence, c.8264_8268del (p.Tyr2755CysfsTer12) is classified as Pathogenic.
Natera, Inc.	RCV000190640	SCV002079360	pathogenic	Ataxia-telangiectasia syndrome	2021-09-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739491	SCV005360488	pathogenic	ATM-related disorder	2024-06-06	no assertion criteria provided	clinical testing	The ATM c.8264_8268del5 variant is predicted to result in a frameshift and premature protein termination (p.Tyr2755Cysfs*12). This variant has previously been reported to be causative for Ataxia Telangiectasia (Stankovic et al. 1998. PubMed ID: 9463314; Barone et al. 2009. PubMed ID: 19431188). Also, this variant was reported in individuals with invasive breast cancer and colon polyps (Susswein LR et al. 2015. PubMed ID: 26681312, Table 1. Hollestelle A et al 2010. PubMed ID: 20346647, Graña B et al 2011. PubMed ID: 21445571, Table 2. Ellingson MS et al 2015. PubMed ID: 26296701). This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181865/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.