ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.640del (p.Ser214fs) (rs786204543)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169254 SCV000220538 likely pathogenic Ataxia-telangiectasia syndrome 2014-07-23 criteria provided, single submitter literature only
GeneDx RCV000494401 SCV000581706 pathogenic not provided 2018-04-27 criteria provided, single submitter clinical testing This deletion of one nucleotide in ATM is denoted c.640delT at the cDNA level and p.Ser214ProfsX16 (S214PfsX16) at the protein level. The normal sequence, with the base that is deleted in brackets, is CTTTTTT[delT]CCAA. The deletion causes a frameshift which changes a Serine to a Proline at codon 214, and creates a premature stop codon at position 16 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 Ser214ProfsX16 is reported to be a Spanish founder variant and has been observed in both individuals with ataxia telangiectasia and breast cancer (Byrd 1996, Mitui 2003, Coutinho 2004, Demuth 2011, Carranza 2017, Tavera-Tapia 2017). We consider this variant to be pathogenic.
Ambry Genetics RCV000561764 SCV000672614 pathogenic Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing The c.640delT pathogenic mutation, located in coding exon 5 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 640, causing a translational frameshift with a predicted alternate stop codon (p.S214Pfs*16). This mutation, either in a homozygous state or in conjunction with another pathogenic mutation in the ATM gene, has been reported in multiple patients diagnosed with ataxia-telangiectasia (Byrd PJ et al. Hum. Mol. Genet. 1996 Jan;5:145-9; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82). 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 RCV000169254 SCV000748987 pathogenic Ataxia-telangiectasia syndrome 2020-07-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser214Profs*16) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous and compound heterozygous states in several individuals affected with ataxia-telangiectasia (PMID: 8789452, 21965147, 12815592, 15039971). It has also been observed in the heterozygous state in individuals affected with breast cancer or referred for cancer panel testing (PMID: 21445571, 26681312). ClinVar contains an entry for this variant (Variation ID: 188895). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000169254 SCV000838473 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000561764 SCV001342222 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169254 SCV001448446 pathogenic Ataxia-telangiectasia syndrome 2020-11-16 criteria provided, single submitter clinical testing Variant summary: ATM c.640delT (p.Ser214ProfsX16) 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 was absent in 251182 control chromosomes. c.640delT has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (e.g. Byrd_1996, Mitui_2003, Coutinho_2004, Demuth_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.