ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.8395_8404del (p.Phe2799fs) (rs786202800)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165801 SCV000216548 pathogenic Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing The c.8395_8404del10 pathogenic mutation, located in coding exon 56 of the ATM gene, results from a deletion of 10 nucleotides at nucleotide positions 8395 to 8404, causing a translational frameshift with a predicted alternate stop codon (p.F2799Kfs*4). This mutation has been reported in cohorts of individuals with classic ataxia-telangiectasia (Broeks A et al. Hum. Mutat. 1998;12:330-7; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50). This pathogenic mutation has also been reported in an individual diagnosed with colon cancer at age 40 whose tumor showed stable MSI and normal IHC (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This pathogenic mutation was detected in two unrelated individuals diagnosed with sporadic pancreatic ductal adenocarcinoma at ages 35 and 55, respectively (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). Of note, this alteration is also designated as 8385del10 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000204163 SCV000260589 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe2799Lysfs*4) in the ATM gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 9887333, 9792409, 10817650, 12815592, 21833744), and colorectal cancer (PMID: 25980754, 27978560). This variant is also known as 839del10 in the literature. ClinVar contains an entry for this variant (Variation ID: 186242). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255017 SCV000321412 pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing This deletion of 10 nucleotides in ATM is denoted c.8395_8404del10 at the cDNA level and p.Phe2799LysfsX4 (F2799KfsX4) at the protein level. The surrounding sequence is TGCC[del10]AAAAG. The deletion causes a frameshift, which changes a Phenylalanine to a Lysine at codon 2799, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.8395_8404del10, also published as 8395del10, has been observed in multiple individuals with Ataxia-telangiectasia as well as two individuals with pancreatic cancer and another with young onset colon cancer (Broeks 1998, Sandoval 1999, Li 2000, Mitui 2003, Ehlayel 2008, Carney 2012, Pearlman 2017, Shindo 2017). Based on currently available evidence, we consider this variant to be pathogenic.
Counsyl RCV000204163 SCV000678030 likely pathogenic Ataxia-telangiectasia syndrome 2015-10-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165801 SCV000687827 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000204163 SCV001163274 pathogenic Ataxia-telangiectasia syndrome criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255017 SCV001246122 pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000204163 SCV001338346 pathogenic Ataxia-telangiectasia syndrome 2020-02-10 criteria provided, single submitter clinical testing Variant summary: ATM c.8395_8404del10 (p.Phe2799LysfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251232 control chromosomes (gnomAD). c.8395_8404del10 has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Nahas_2009, Mitui_2003, Soukupova_2011). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated the most pronounced variant effect results in <10% of normal phosphorylation activity (Nahas_2009). Five 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 (4x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255017 SCV001447197 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001574077 SCV001797302 pathogenic Breast carcinoma 2021-08-20 no assertion criteria provided clinical testing Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative

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