Submissions for variant NM_000051.4(ATM):c.742C>T (p.Arg248Ter)

gnomAD frequency: 0.00001  dbSNP: rs730881336

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211945	SCV000209680	pathogenic	not provided	2024-02-21	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 in the heterozygous state in individuals with ATM-related cancers referred for genetic testing at GeneDx and in published literature (PMID: 25186627, 27433846, 27732944, 28281021); Observed in the compound heterozygous state with a second ATM variant in patients with ataxia telangiectasia in published literature, but it was not determined whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 9711876, 16266405, 30402232); 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: 25186627, 16266405, 34404412, 32826389, 32875559, 29922827, 9711876, 25525159, 25855536, 26681312, 25428789, 27433846, 28281021, 27732944, 30402232, 31447099, 31589614, 32427313, 35441217, 37685988, 37732318, 35938029, 36243179, 33309985, 36988593)
Ambry Genetics	RCV000159678	SCV000217771	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-02	criteria provided, single submitter	clinical testing	The p.R248* pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 742. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation was identified in the compound heterozygous state in three individuals with ataxia telangiectasia, although phase was not confirmed (Sasaki T et al. Hum. Mutat. 1998;12:186-95; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69:657-64). This alteration was also reported in 1/10,030 individuals undergoing hereditary cancer panel testing through a clinical laboratory (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32) and in one individual from a cohort of 692 men with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). 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	RCV000410046	SCV000485320	likely pathogenic	Ataxia-telangiectasia syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515228	SCV000611167	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410046	SCV000622747	pathogenic	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg248*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with ataxia telangiectasia (PMID: 9711876, 16266405, 26681312, 27433846, 28281021). ClinVar contains an entry for this variant (Variation ID: 181913). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000159678	SCV000687770	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 7 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 individuals affected with breast cancer (PMID: 26681312, 28281021) and prostate cancer (PMID: 27433846). This variant has been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 9711876, 16266405, 30402232). This variant has been identified in 2/245760 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	RCV000709708	SCV000839882	pathogenic	Familial cancer of breast	2017-05-24	criteria provided, single submitter	clinical testing	This c.742C>T (p.Arg248*) variant in the ATM gene has previously been reported in two Japanese patients with ataxia telangiectasia [PMID 9711876]. Both patients were compound heterozygous for this variant and a loss of function variant [PMID 9711876]. This c.742C>T encodes for a premature stop codon in exon 7 at amino acid position 248 of the ATM protein, leading to a loss of function of the protein. This variant has been observed in one heterozygous East Asian individual in the ExAC database (http://exac.broadinstitute.org/variant/11-108115594-C-T). It is thus classified as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410046	SCV001363667	pathogenic	Ataxia-telangiectasia syndrome	2020-12-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.742C>T (p.Arg248X) 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 allele was found at a frequency of 8e-06 in 251010 control chromosomes. c.742C>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Micol_2011, Sasaki_1998, Mitui_2005, Ye_2018), Breast Cancer (Susswein_2015), and Prostate Cancer (Pritchard_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=6)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000410046	SCV002018962	pathogenic	Ataxia-telangiectasia syndrome	2019-06-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000211945	SCV004042524	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ATM: PM3:Very Strong, PVS1, PM2
Baylor Genetics	RCV000709708	SCV004206399	pathogenic	Familial cancer of breast	2023-10-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000709708	SCV004931088	pathogenic	Familial cancer of breast	2024-01-11	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.
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000410046	SCV000999057	pathogenic	Ataxia-telangiectasia syndrome	2019-11-20	no assertion criteria provided	clinical testing	The patient has another variant on the other allele (arr[GRCh37] 11q22.3(108151766-108183226)x1, 31460 bp).
Laboratory for Genotyping Development, RIKEN	RCV003162669	SCV002758076	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research