Submissions for variant NM_000051.4(ATM):c.1464G>A (p.Trp488Ter)

dbSNP: rs377597949

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001011523	SCV001171854	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-15	criteria provided, single submitter	clinical testing	The p.W488* pathogenic mutation (also known as c.1464G>A), located in coding exon 9 of the ATM gene, results from a G to A substitution at nucleotide position 1464. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This alteration was reported in trans with a different pathogenic ATM mutation in two siblings with a clinical diagnosis of ataxia-telangiectasia (Huang Y et al. Neuromolecular Med., 2013 Sep;15:536-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In additional to the clinical information 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059130	SCV001223740	pathogenic	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp488*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T) (PMID: 23807571). ClinVar contains an entry for this variant (Variation ID: 819185). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814257	SCV001755560	pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001059130	SCV002500068	pathogenic	Ataxia-telangiectasia syndrome	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1464G>A (p.Trp488X) 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 251336 control chromosomes (gnomAD). c.1464G>A has been reported in the literature in individuals affected with Ataxia-Telangiectasia and Breast cancer (Huang_2013, Palmer_2020). Additionally, another variant (c.1463G>A) resulted in p.Trp488X and has been observed in individuals affected with Ataxia-Telangiectasia (Cavalieri_2006, Magliozzi_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV004030322	SCV004931933	pathogenic	Familial cancer of breast	2024-01-16	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.
GeneDx	RCV004702577	SCV005201680	pathogenic	not provided	2024-01-24	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; Identified in the heterozygous state in an individual with breast cancer (PMID: 32427313); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 16941484, 37564729, 17124347, 25614872, 32427313, 23807571)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258178	SCV001435067	uncertain significance	Ataxia-telangiectasia syndrome; Breast cancer, susceptibility to		flagged submission	clinical testing