ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1931C>A (p.Ser644Ter) (rs768362387)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222313 SCV000278014 pathogenic Hereditary cancer-predisposing syndrome 2018-09-25 criteria provided, single submitter clinical testing The p.S644* pathogenic mutation (also known as c.1931C>A), located in coding exon 12 of the ATM gene, results from a C to A substitution at nucleotide position 1931. This changes the amino acid from a serine to a stop codon within coding exon 12. This mutation has been reported in conjunction with a second pathogenic mutation in an individual with ataxia telangiectasia (A-T) (Li A and Swift M. Am J Med Genet. 2000 May 29;92(3):170-7) as well as in individuals with pancreatic cancer and in individuals with gastric cancer (Grant RC et al. Hum Genomics. 2013 Apr 5;7:11; Helgason H et al Nat. Genet. 2015 Aug;47(8):906-10). 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.
GeneDx RCV000482158 SCV000568316 pathogenic not provided 2017-06-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.1931C>A at the cDNA level and p.Ser644Ter (S644X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with Ataxia-Telangiectasia, in the presumed compound heterozygous state (Li 2000), as well as in individuals with pancreatic and gastric cancer (Grant 2013, Helgason 2015, Roberts 2016). We consider this variant to be pathogenic.
Counsyl RCV000576759 SCV000678107 likely pathogenic Ataxia-telangiectasia syndrome 2017-06-14 criteria provided, single submitter clinical testing
Invitae RCV000576759 SCV000825216 pathogenic Ataxia-telangiectasia syndrome 2020-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser644*) 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 individuals affected with gastric cancer (PMID: 26098866) and pancreatic cancer (PMID: 23561644, 25479140). Additionally this variant has been reported in combination with another ATM variant in an individual affected with ataxia telangiectasia (PMID: 10817650). ClinVar contains an entry for this variant (Variation ID: 233607). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762815 SCV000893173 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000222313 SCV001734339 pathogenic Hereditary cancer-predisposing syndrome 2020-09-28 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 13 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with pancreatic cancer (PMID: 23561644, 25479140) and has been shown to be associated with an increased risk of gastric cancer in the Icelandic population (PMID: 26098866). This variant has been reported in an individual affected with ataxia-telangiectasia (PMID: 10817650). This variant has not been identified 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.

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