Submissions for variant NM_000051.4(ATM):c.1339C>T (p.Arg447Ter)

gnomAD frequency: 0.00001  dbSNP: rs587779815

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211960	SCV000149050	pathogenic	not provided	2023-02-01	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); Observed with a pathogenic variant on the opposite allele (in trans) in individuals with ataxia telangiectasia in published literature (Gilad et al., 1996; Fares et al., 2004; Perez-Villena et al., 2013; Hoche et al., 2014; Kraus et al., 2014); Observed in individuals with breast, prostate, and other cancers (Pritchard et al., 2016; Susswein et al., 2016; Barbalho et al., 2021); 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: 27433846, 15164409, 25037873, 26681312, 32522261, 29922827, 35047863, 25525159, 8845835, 23612382, 24763289, 24568663, 26778106, 24789685, 28152038, 28779002, 30322717, 31447099, 31589614, 32427313, 35260754, 35441217, 35586824, 29625052, 30130155, 25303977, 35155181, 36140756, 30772474, 31948886)
Ambry Genetics	RCV000115141	SCV000172928	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-18	criteria provided, single submitter	clinical testing	The p.R447* pathogenic mutation (also known as c.1339C>T), located in coding exon 9 of the ATM gene, results from a C to T substitution at nucleotide position 1339. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in several individuals with classic ataxia-telangiectasia including three Druze families, suggesting it is a founder mutation in the Druze population (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Fares F et al. Prenat. Diagn. 2004 May;24:358-62). It has also been reported in individuals with breast, ovarian, or prostate cancer (Susswein LR et al. Genet. Med., 2016 08;18:823-32; Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53; Decker B et al. J. Med. Genet., 2017 Nov;54:732-741). 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	RCV000169409	SCV000220813	likely pathogenic	Ataxia-telangiectasia syndrome	2014-10-17	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000115141	SCV000537674	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 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 observed in individuals affected with autosomal recessive ataxia-telangiectasia, with several individuals confirmed to be homozygotes or compound heterozygotes with a second pathogenic variant in trans (PMID: 8845835, 15164409, 23612382, 24789685, 25037873), indicating that this variant contributes to disease. This variant has also been reported in individuals affected with breast cancer, ovarian cancer, prostate cancer, and/or underwent hereditary cancer multigene panel testing (PMID: 28779002, 24763289, 26681312, 27433846, 33471991). This variant has been identified in 2/251290 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169409	SCV000622246	pathogenic	Ataxia-telangiectasia syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg447*) 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 (rs587779815, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and ovarian and prostate cancer (PMID: 8845835, 15164409, 23612382, 24789685, 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 127337). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169409	SCV000694179	pathogenic	Ataxia-telangiectasia syndrome	2016-12-05	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.1339C>T (p.Arg447X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3049C>T/p.Gln1017X, c.4396C>T/p.Arg1466X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121264 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant has been reported as germline variant in mutliple Ataxia-Telangiectasia patients in autosomal recessive inheritance and patients with ovarian cancer, chronic lymphocyti leukemia or prostate cancer in autosomal dominant inheritance. It also has been reported in at least one patient with aggressive cutaneous squamous cell carcinoma as a somatic variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258117	SCV001434990	pathogenic	Ataxia-telangiectasia syndrome; Breast cancer, susceptibility to	2018-10-08	criteria provided, single submitter	clinical testing	The c.1339C>T (p.Arg447*) 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 an extremely low frequency in large databases of genetic variation in the general population. Mono-allelic variants in the ATM gene have been associated with susceptibility to breast cancer (MIM #114480) whereas bi-allelic variants in this gene are associated with Ataxia-telangiectasia (MIM #208900). This variant has been reported in several individuals affected with ataxia-telangiectasia (PMID: 8845835, 15164409) and in patients affected with cancer (PMID: 26681312, 27433846). Therefore, the c.1339C>T (p.Arg447*) variant in the ATM gene is classified as pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000211960	SCV002502232	pathogenic	not provided	2022-03-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115141	SCV002530287	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	curation
3billion	RCV000169409	SCV002573174	pathogenic	Ataxia-telangiectasia syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000127337 / PMID: 8845835). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000169409	SCV003811079	pathogenic	Ataxia-telangiectasia syndrome	2023-02-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460799	SCV004207036	pathogenic	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003460799	SCV004931864	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.
GenomeConnect, ClinGen	RCV000211960	SCV000607155	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000169409	SCV002090956	pathogenic	Ataxia-telangiectasia syndrome	2020-10-29	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162534	SCV002758212	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research