Submissions for variant NM_000051.4(ATM):c.5188C>T (p.Arg1730Ter)

gnomAD frequency: 0.00001  dbSNP: rs764389018

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169451	SCV000220872	likely pathogenic	Ataxia-telangiectasia syndrome	2014-11-11	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169451	SCV000261713	pathogenic	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1730*) 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 (rs764389018, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10425038, 12815592, 21792198, 22213089). ClinVar contains an entry for this variant (Variation ID: 189054). 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.
Ambry Genetics	RCV000570483	SCV000665457	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-29	criteria provided, single submitter	clinical testing	The p.R1730* pathogenic mutation (also known as c.5188C>T), located in coding exon 34 of the ATM gene, results from a C to T substitution at nucleotide position 5188. This changes the amino acid from an arginine to a stop codon within coding exon 34. This mutation has been reported in individuals and families with ataxia telangiectasia (A-T), including in homozygous individuals with no ATM protein expression (Castellví-Bel S et al, Hum. Mutat. 1999 ; 14(2):156-62; Mitui M et al, Hum. Mutat. 2003 Jul; 22(1):43-50; Carranza D et al. Neuromolecular Med. 2017 Mar;19(1):161-174; Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71). 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.
Color Diagnostics, LLC DBA Color Health	RCV000570483	SCV000682254	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 35 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 the homozygous and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 10425038, 12815592, 21665257, 21792198, 22213089). This variant has also been identified in 2/251138 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.
GeneDx	RCV000657610	SCV000779352	pathogenic	not provided	2018-02-12	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5188C>T at the cDNA level and p.Arg1730Ter (R1730X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the homozygous or compound heterozygous state in several individuals with Ataxia-telangiectasia (Mitui 2003, Mitui 2005, Carranza 2017, van Os 2017) and is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169451	SCV002015009	pathogenic	Ataxia-telangiectasia syndrome	2021-10-22	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5188C>T (p.Arg1730X) 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 251138 control chromosomes (gnomAD). c.5188C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia in both the homozygous and compound heterozygous state (example, Reiman_2011, Verhagen_2012, Driessen_2013 and Carranza_2017). These data indicate that the variant is associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003468844	SCV004210170	pathogenic	Familial cancer of breast	2024-02-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468844	SCV004931033	pathogenic	Familial cancer of breast	2024-01-25	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.	RCV000169451	SCV001452311	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162723	SCV002758098	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research