Submissions for variant NM_000051.4(ATM):c.5798G>A (p.Trp1933Ter)

gnomAD frequency: 0.00001  dbSNP: rs876658740

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218884	SCV000274398	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.W1933* pathogenic mutation (also known as c.5798G>A), located in coding exon 38 of the ATM gene, results from a G to A substitution at nucleotide position 5798. This changes the amino acid from a tryptophan to a stop codon within coding exon 38. This mutation has been reported in an individual with a personal and family history of breast cancer (Meiss AE et al. Hum. Pathol., 2018 12;82:20-31). 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.
Counsyl	RCV000409971	SCV000486860	likely pathogenic	Ataxia-telangiectasia syndrome	2016-08-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000627198	SCV000748182	pathogenic	not provided	2023-10-18	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; 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; Observed in individuals with breast or ovarian cancer (Lilyquist et al., 2017; Meiss et al., 2018; Palmer et al., 2020); This variant is associated with the following publications: (PMID: 29958926, 32427313, 28888541)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409971	SCV000833572	pathogenic	Ataxia-telangiectasia syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1933*) 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 variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 230743). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000627198	SCV002570209	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469013	SCV004210101	likely pathogenic	Familial cancer of breast	2023-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000627198	SCV004221188	pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	The ATM c.5798G>A (p.Trp1933*) variant causes the premature termination of ATM protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 28888541 (2017)), and breast cancer (PMID: 29958926 (2018), 32427313 (2020)). This variant has also been reported in an unaffected individual (PMID: 32427313 (2020)). The frequency of this variant in the general population, 0.000013 (2/152042 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003469013	SCV004931160	pathogenic	Familial cancer of breast	2024-01-26	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.