Submissions for variant NM_000051.4(ATM):c.1290_1291del (p.Cys430_Glu431delinsTer)

dbSNP: rs587781598

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129663	SCV000184461	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-31	criteria provided, single submitter	clinical testing	The c.1290_1291delTG pathogenic mutation (also known as p.C430*), located in coding exon 9 of the ATM gene, results from a deletion of 2 nucleotides between positions 1290 and 1291. This changes the amino acid from a cysteine to a stop codon within coding exon 9. This alteration was reported in conjunction with a second pathogenic alteration in an ataxia-telangiectasia family (Stankovic T et al. Am J Hum Genet. 1998 Feb;62(2):334-45). This alteration has also been reported in a woman with a mild ataxia-telangiectasia presentation in conjunction with a second pathogenic alteration. Functional analyses of LCL and fibroblasts from this individual revealed absent ATM kinase activity, absent ATM protein expression, and increased radiosensitivity (Worth et al. Mov. Disord. 2013 Apr;28(4):524-8). 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	RCV000236686	SCV000292788	pathogenic	not provided	2023-05-03	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); 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: 23143971, 9463314, 10817650, 28152038, 28779002, 31980526, 29922827, 35626031, 37024097)
Counsyl	RCV000410187	SCV000485526	likely pathogenic	Ataxia-telangiectasia syndrome	2015-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410187	SCV000547149	pathogenic	Ataxia-telangiectasia syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys430*) 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 (rs587781598, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with ataxia-telangiectasia (PMID: 9463314, 23143971). ClinVar contains an entry for this variant (Variation ID: 141241). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410187	SCV001821317	pathogenic	Ataxia-telangiectasia syndrome	2021-08-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1290_1291delTG (p.Cys430X) 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 4e-06 in 250386 control chromosomes. c.1290_1291delTG has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Stankovic_1998, Worth_2013, Li_2000). One patient had mild AT, despite functional analysis of LCL and fibroblasts from this individual revealing absent ATM kinase activity, absent ATM protein expression, and increased radiosensitivity (Worth_2013). Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003467117	SCV004212214	pathogenic	Familial cancer of breast	2022-09-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236686	SCV004243409	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467117	SCV004932242	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.
Natera, Inc.	RCV000410187	SCV002090912	pathogenic	Ataxia-telangiectasia syndrome	2021-07-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551245	SCV004732625	pathogenic	ATM-related disorder	2023-11-30	no assertion criteria provided	clinical testing	The ATM c.1290_1291delTG variant is predicted to result in premature protein termination (p.Cys430*). This variant has been reported in multiple individuals with autosomal recessive ataxia telangiectasia (Table 1, Stankovic et al. 1998. PubMed ID: 9463314; Worth et al. 2012. PubMed ID: 23143971) or autosomal dominant susceptibility to breast and/or ovarian cancer (Table S2, Espinel et al. 2022. PubMed ID: 35626031). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141241/). An in vitro experimental study suggests this variant increases cells radiosensitivity (Figure 2, Worth et al. 2012. PubMed ID: 23143971). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.