Submissions for variant NM_000051.4(ATM):c.802C>T (p.Gln268Ter)

dbSNP: rs557012154

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169336	SCV000220682	likely pathogenic	Ataxia-telangiectasia syndrome	2014-09-10	criteria provided, single submitter	literature only
Ambry Genetics	RCV000222842	SCV000278020	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.Q268* pathogenic mutation (also known as c.802C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 802. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation has been previously identified in ataxia-telangiectasia patients (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31). 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.
GeneDx	RCV000519059	SCV000617365	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Teraoka 1999); Published functional studies demonstrate a damaging effect: loss of kinase activity (Carranza 2017); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12552559, 27664052, 10330348, 35284771)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169336	SCV000694369	pathogenic	Ataxia-telangiectasia syndrome	2022-01-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.802C>T (p.Gln268X) 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 7.8e-06 in 255540 control chromosomes (gnomAD). c.802C>T has been reported in the literature in compound heterozygous individuals affected with Ataxia-Telangiectasia (examples: Teraoka_1999, Buzin_2003 and Carranza_2017). These data indicate that the variant is associated with disease. Functional analysis using nested-PCR cDNAs of a cell line containing this variant showed missplicing of exon 9 (Teraoka_1999). The effect was the partial skipping of the exon. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169336	SCV000749006	pathogenic	Ataxia-telangiectasia syndrome	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln268*) 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 (rs557012154, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348, 12552559). ClinVar contains an entry for this variant (Variation ID: 188961). 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	RCV000222842	SCV001347034	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-16	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 observed in multiple individuals affected with autosomal recessive ataxia telangiectasia in the compound heterozygous state with a second pathogenic variant (PMID: 10330348, 12552559, 27664052, 35284771), indicating that this variant contributes to disease. This variant has been identified in 1/251050 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.
CeGaT Center for Human Genetics Tuebingen	RCV000519059	SCV002585344	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	ATM: PVS1, PM2
Baylor Genetics	RCV003468841	SCV004210290	pathogenic	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468841	SCV004931271	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.