Submissions for variant NM_000051.4(ATM):c.5908C>T (p.Gln1970Ter)

gnomAD frequency: 0.00021  dbSNP: rs587781722

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129909	SCV000184727	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-02	criteria provided, single submitter	clinical testing	The p.Q1970* pathogenic mutation (also known as c.5908C>T), located in coding exon 38 of the ATM gene, results from a C to T substitution at nucleotide position 5908. This changes the amino acid from a glutamine to a stop codon within coding exon 38. In one study, the p.Q1970* mutation accounted for 56% (30/54) of pathogenic alleles detected in Costa Rican individuals with ataxia-telangiectasia and was recognized as a founder mutation in the Costa Rican population (Telatar M et al. Am. J. Hum. Genet. 1998 Jan; 62:86-97). This mutation was detected in the homozygous state in an individual with prominent myoclonus, marked oculomotor apraxia, and elevated alpha-fetoprotein level function (Termsarasab P et al. Tremor Other Hyperkinet Mov (NY). 2015;5:298). This variant has also been reported in patients diagnosed with pancreatic cancer (Hutchings D et al. Mod Pathol. 2019 12;32:1806-1813; Lowery MA et al. J Natl Cancer Inst. 2018 10;110:1067-1074). 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	RCV000200350	SCV000253741	pathogenic	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1970*) 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 present in population databases (rs587781722, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9443866, 12815592). ClinVar contains an entry for this variant (Variation ID: 141404). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000235704	SCV000293233	pathogenic	not provided	2021-11-29	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; This variant is associated with the following publications: (PMID: 12815592, 18634022, 25793145, 25525159, 9443866, 26886021, 15498871, 23774824, 29506128, 31447099, 31285527)
Counsyl	RCV000200350	SCV000485172	pathogenic	Ataxia-telangiectasia syndrome	2016-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200350	SCV000694305	pathogenic	Ataxia-telangiectasia syndrome	2016-12-09	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.5908C>T (p.Gln1970X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP). The variant of interest has been reported in multiple affected individuals via publications and has been implicated to be a Costa Rican founder mutation. In addition, multiple clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
Fulgent Genetics, Fulgent Genetics	RCV000762823	SCV000893181	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129909	SCV000911668	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 39 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 both in the homozygous and compound heterozygous states in multiple individuals affected with ataxia telangiectasia (PMID: 9443866, 12815592, 25793145) and has been reported to be a recurring mutation in the Costa Rican population. This variant has been identified in 8/250774 chromosomes (8/34530 Latino chromosomes) 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258121	SCV001434994	pathogenic	Ataxia-telangiectasia syndrome; Breast cancer, susceptibility to	2018-10-02	criteria provided, single submitter	clinical testing	The c.5908C>T (p.Gln1970*) variant in the ATM gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has a low frequency in large databases of genetic variation in the general population. This variant has been reported in multiple patients with Ataxia-telangiectasia in both homozygous and compound heterozygous state and is reported as the most common pathogenic ATM variant in Costa Rica (PMID 9443866, 9682216, 12815592 and 25793145). Bi-allelic variants in the ATM gene are associated with Ataxia-telangiectasia (MIM #208900). Therefore, the c.5908C>T (p.Gln1970*) variant in the ATM gene is classified as pathogenic.
Athena Diagnostics	RCV000235704	SCV001879516	pathogenic	not provided	2022-05-17	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Sema4, Sema4	RCV000129909	SCV002537461	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-11	criteria provided, single submitter	curation
Baylor Genetics	RCV003460905	SCV004207026	pathogenic	Familial cancer of breast	2024-03-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235704	SCV004221196	pathogenic	not provided	2022-05-17	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Additionally, the variant was found in at least one symptomatic patient, and found in general population data at a frequency that is consistent with pathogenicity.
Myriad Genetics, Inc.	RCV003460905	SCV004933061	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.
Natera, Inc.	RCV000200350	SCV001457396	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing