ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1931C>A (p.Ser644Ter)

dbSNP: rs768362387
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Total submissions: 8
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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 2021-12-23 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 2024-02-26 criteria provided, single submitter clinical testing Nonsense 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; Observed with a second ATM variant in a patient with ataxia-telangiectasia (PMID: 10817650); Observed in the heterozygous state in individuals with ATM-related cancers (PMID: 23561644, 26658419); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27304073, 25525159, 23561644, 26546047, 26098866, 28246015, 30507471, Jones2018[article], 25479140, 10817650, 26658419)
Counsyl RCV000576759 SCV000678107 likely pathogenic Ataxia-telangiectasia syndrome 2017-06-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000576759 SCV000825216 pathogenic Ataxia-telangiectasia syndrome 2023-04-25 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 233607). This premature translational stop signal has been observed in individual(s) with gastric cancer, pancreatic cancer, and ataxia telangiectasia (PMID: 10817650, 23561644, 25479140, 26098866). This variant is not present in population databases (gnomAD no frequency). 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. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872).
Fulgent Genetics, Fulgent Genetics RCV000762815 SCV000893173 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235146 SCV003934459 pathogenic Malignant tumor of breast 2023-05-30 criteria provided, single submitter clinical testing Variant summary: ATM c.1931C>A (p.Ser644X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanisms for disease. Another variant resulting in the same termination codon is classified as pathogenic in ClinVar (c.1931C>G). The variant was absent in 251128 control chromosomes (gnomAD). c.1931C>A has been reported in the literature in compound heterozygous individual(s) affected with Ataxia-Telangiectasia (Li_2000). The following publication has been ascertained in the context of this evaluation (PMID: 10817650). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc. RCV004020689 SCV004931354 pathogenic Familial cancer of breast 2024-01-17 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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