rs730881294
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_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
Consequence
NM_000051.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
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: 5AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250752Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135526
GnomAD4 exome AF: 0.00000414 AC: 6AN: 1449180Hom.: 0 AF XY: 0.00000277 AC XY: 2AN XY: 721994
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74410
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at