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

dbSNP: rs786202800

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165801	SCV000216548	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-28	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) and 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	2024-01-30	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. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs761367329, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9792409, 9887333, 10817650, 12815592, 21833744, 25980754, 27978560). This variant is also known as 839del10. ClinVar contains an entry for this variant (Variation ID: 186242). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000255017	SCV000321412	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in individuals with ATM-related cancers (Pearlman 2017, Shindo 2017); Also known as 8395del10; This variant is associated with the following publications: (PMID: 10817650, 34637943, 25980754, 15039971, 12815592, 28767289, 27978560, 21833744, 30287823, 18718650, 30322717, 31285527, 9792409, 9887333, 22649200, 31948886, 26896183, 29625052, 33919281, 33436325, 32888943)
Counsyl	RCV000204163	SCV000678030	likely pathogenic	Ataxia-telangiectasia syndrome	2015-10-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165801	SCV000687827	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This variant deletes 10 nucleotides in exon 57 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 10817650, 12815592, 21665257, 21833744). This variant has also been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 27978560) and pancreatic cancer (PMID: 28767289, 35892882). This variant has been identified in 5/251232 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.
Baylor Genetics	RCV000204163	SCV001163274	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255017	SCV001246122	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	ATM: PVS1, PM2
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
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002221503	SCV002499139	pathogenic	Familial cancer of breast	2022-03-21	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Sema4, Sema4	RCV000165801	SCV002527274	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000255017	SCV004024729	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000204163	SCV004047767	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	The frame (c.8395_8404del) variant has been reported previously in patients affected with Ataxia-telangiectasia (Li A, Swift M., 200). The p.Phe2799LysfsTer4 variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. This variant causes a frameshift starting with codon Phenylalanine 2799, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Phe2799LysfsTer4. Loss-of-function variants in ATM are known to be pathogenic (Huang et. al., 2013). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV002221503	SCV004208856	pathogenic	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000255017	SCV004224283	likely pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing	PM3, PVS1
Myriad Genetics, Inc.	RCV002221503	SCV004930591	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.
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
Natera, Inc.	RCV000204163	SCV002079483	pathogenic	Ataxia-telangiectasia syndrome	2020-08-20	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV002221503	SCV002589042	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162705	SCV002758325	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research