Submissions for variant NM_000051.4(ATM):c.7913G>A (p.Trp2638Ter)

gnomAD frequency: 0.00006  dbSNP: rs377349459

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129649	SCV000184447	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	clinical testing	The p.W2638* pathogenic mutation (also known as c.7913G>A), located in coding exon 52 of the ATM gene, results from a G to A substitution at nucleotide position 7913. This changes the amino acid from a tryptophan to a stop codon within coding exon 52. This mutation has been reported in a compound heterozygous or homozygous state in multiple individuals with classic ataxia-telangiectasia (Sasaki T et al. Hum. Mutat. 1998;12:186-95; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Coutinho G et al. Am. J. Med. Genet. A. 2004 Apr;126A:33-40; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82) and has been identified in breast and prostate cancer cohorts (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). 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	RCV000212077	SCV000209648	pathogenic	not provided	2020-12-11	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 (Pritchard 2016, Adedokun 2020); This variant is associated with the following publications: (PMID: 25525159, 23774824, 9711876, 28008555, 27433846, 26681312, 24681528, 28301456, 16953663, 28152038, 25614872, 23807571, 12815592, 15039971, 31871109, 30370249, 21965147, 32832836)
Counsyl	RCV000169621	SCV000221148	likely pathogenic	Ataxia-telangiectasia syndrome	2015-02-19	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169621	SCV000253746	pathogenic	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2638*) 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 (rs377349459, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia, colon cancer, and/or prostate cancer (PMID: 9711876, 12815592, 15039971, 21965147, 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 141233). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129649	SCV000687802	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 53 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 breast cancer, prostate cancer, colorectal cancer, melanoma (PMID: 26681312, 27433846, 28008555, 31871109, 35353237; DOI: 10.21203/rs.3.rs-1065243/v1), and in homozygous and compound heterozygous carriers affected with ataxia-telangiectasia (PMID: 9711876, 12815592, 15039971, 21965147). Haplotype analyses suggest this variant may be a founder mutation in individuals of African ancestry (PMID: 12815592, 15039971). This variant has been identified in 5/281730 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169621	SCV000694363	pathogenic	Ataxia-telangiectasia syndrome	2017-05-15	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.7913G>A (p.Trp2638X) 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.8264_8268delATAAG, p.Tyr2755fsX12; c.8266A>T, p.Lys2756X; c.8287C>T, p.Arg2763X; c.8977C>T, p.Arg2993X). The variant of interest has been found in ExAC in 1/120514 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant was reported in several patients with Ataxia Telangiectasia (A-T) in homozygous state as well as in compound heterozygous state with other pathogenic/ likely pathogenic variants (Sasaki_Hum Mutat_1998, Coutinho_AmJMedGenet_2004, Demuth_Neurogenetics_2011, Nakamura_Mol Genet Genomic Med_2014). Protein expression and ATM-dependent kinase activity assays from patient cells carrying this variant in heterozygous state and compound heterozygous state with another truncating variant are consistent with the predicted outcome (Fernet_BrJC_2004, Nakamura_Mol Genet Genomic Med_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000169621	SCV000838603	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768151	SCV000898530	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-11-23	criteria provided, single submitter	clinical testing	ATM NM_000051 exon 53 p.Trp2638* (c.7913G>A): This variant has been identified as homozygous or compound heterozygous in at least 6 individuals with ataxia telangiectasia (Sasaki 1998 PMID:9711876, Mitui 2003 PMID:12815592, Coutinho 2004 PMID:15039971, Demuth 2011 PMID:21965147). This variant was also identified in at least 2 individuals with colon or prostate cancer (Pritchard 2016 PMID:27433846, Susswein 2016 PMID:26681312). This variant is present in 4/24010 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs377349459). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:141233). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Huang 2013 PMID:23807571) . In summary, this variant is classified as pathogenic.
Athena Diagnostics	RCV000212077	SCV001475571	pathogenic	not provided	2020-02-11	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Revvity Omics, Revvity	RCV000169621	SCV002020077	pathogenic	Ataxia-telangiectasia syndrome	2019-05-06	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251994	SCV002523255	pathogenic	See cases	2019-09-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM3
Sema4, Sema4	RCV000129649	SCV002537756	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-30	criteria provided, single submitter	curation
Baylor Genetics	RCV003460899	SCV004205102	pathogenic	Familial cancer of breast	2024-03-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212077	SCV004222229	pathogenic	not provided	2020-02-11	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of ATM protein synthesis. The frequency of this variant in the general population, 0.00016 (4/24942 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 31871109 (2019), 28008555 (2017), prostate cancer (PMID: 27433846 (2016), 28008555 (2017)), and colon cancer (PMID: 26681312 (2015)). The variant has been detected in individuals with ataxia-telangiectasia. Those individuals were compound heterozygous for the variant and an ATM pathogenic or likely pathogenic variant (PMID: 9711876 (1998), 15039971 (2004), 21965147 (2011)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003460899	SCV004933461	pathogenic	Familial cancer of breast	2024-02-01	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.	RCV000169621	SCV002075976	pathogenic	Ataxia-telangiectasia syndrome	2021-04-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739433	SCV005360733	pathogenic	ATM-related disorder	2024-03-15	no assertion criteria provided	clinical testing	The ATM c.7913G>A variant is predicted to result in premature protein termination (p.Trp2638*). This variant has previously been reported in the homozygous and compound heterozygous states in individuals with ataxia telangiectasia (Sasaki et al. 1998. PubMed ID: 9711876; Coutinho et al. 2004. PubMed ID: 15039971; Demuth et al. 2011. PubMed ID: 21965147). This variant has also been reported in the heterozygous state in individuals with breast, ovarian, prostate and colorectal cancers (Susswein et al. 2015. PubMed ID: 26681312; Pritchard et al. 2016. PubMed ID: 27433846; Pritzlaff et al. 2016. PubMed ID: 28008555; Adedokun et al. 2019. PubMed ID: 31871109). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD and is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141233/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.