Submissions for variant NM_000051.4(ATM):c.1402_1403del (p.Lys468fs)

gnomAD frequency: 0.00004  dbSNP: rs587781347

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129125	SCV000183842	pathogenic	Hereditary cancer-predisposing syndrome	2012-11-19	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl	RCV000169588	SCV000221096	likely pathogenic	Ataxia-telangiectasia syndrome	2015-01-28	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169588	SCV000260603	pathogenic	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys468Glufs*18) 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 (rs587781347, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast, rectal, prostate or ovarian cancer (PMID: 9792409, 12552559, 20308662, 22649200, 23322442, 24733792, 25892863, 26094658, 27433846, 30322717, 31815095). ClinVar contains an entry for this variant (Variation ID: 140889). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000236583	SCV000292779	pathogenic	not provided	2022-12-27	criteria provided, single submitter	clinical testing	Frameshift 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; 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: 23322442, 22649200, 25892863, 26094658, 20308662, 32866655, 24733792, 10817650, 9792409, 12552559, 23807571, 24763289, 23264026, 21933854, 23726790, 25101980, 27433846, 28779002, 28152038, 30322717, 30607632, 31815095, 32318955, 31447099, 31980526, 26896183, 31691010, 32761968, 34247626, 21665257, 35171259, 34771502, 34917121, 33277227, 30613976, 28724667, 29922827)
Color Diagnostics, LLC DBA Color Health	RCV000129125	SCV000681977	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 of the ATM gene, creating a frameshift and 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 state and in the compound heterozygous state with an additional ATM pathogenic variant in individuals affected with ataxia telangiectasia (PMID: 9792409, 20308662, 21665257, 22649200, 23322442, 23726790, 23807571). This variant has also been reported in individuals affected with breast cancer and ovarian cancer (PMID: 24733792, 26094658, 31815095). This variant has been identified in 13/282780 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	RCV000169588	SCV001426959	pathogenic	Ataxia-telangiectasia syndrome	2020-07-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1402_1403delAA (p.Lys468GlufsX18) 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-05 in 251414 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.1402_1403delAA has been reported in the literature in homozygous and compound heterozygous genotypes among multiple individuals affected with Ataxia-Telangiectasia (example, Broeks_1998, Lin_2010, Buzin_2003, Carney_2012, Jeddane_2013), and in heterozygosity among multiple individuals with a variety of cancers, such as breast and ovarian (example, Kurian_2015, Alorafi_2015, Manchana_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Carney_2012). The most pronounced variant effect results in a complete absence of ATM protein as measured by western blot and no ATM activity. 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 (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000236583	SCV001714394	pathogenic	not provided	2023-02-08	criteria provided, single submitter	clinical testing	PM3_strong, PVS1
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV002285143	SCV002575017	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-09-26	criteria provided, single submitter	research	PVS1, PS3_Moderate, PS4_Moderate (for AD cancer risk) or PM3_VeryStrong (for AR ataxia-telangiectasia), PM2 (for AR only)
MGZ Medical Genetics Center	RCV002288622	SCV002580771	pathogenic	Familial cancer of breast	2022-04-28	criteria provided, single submitter	clinical testing
3billion	RCV000169588	SCV003841509	pathogenic	Ataxia-telangiectasia syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This homozygous variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000140889 / PMID: 9792409). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV002288622	SCV004203816	pathogenic	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236583	SCV004219970	pathogenic	not provided	2015-12-18	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of ATM protein synthesis. In addition, it has been reported in individuals affected with breast and ovarian cancer, as well as ataxia-telangiectasia, in the published literature (PMID: 31815095 (2019), 26094658 (2015), 20308662 (2010), 9792409 (1998)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing ATM related cancers.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492585	SCV004240303	pathogenic	Breast and/or ovarian cancer	2022-10-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288622	SCV004931065	pathogenic	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002288622	SCV005402317	pathogenic	Familial cancer of breast	2024-06-04	criteria provided, single submitter	clinical testing	The ATM c.1402_1403del (p.Lys468GlufsTer18) change deletes two nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in the homozygous and compound heterozygous state in individuals with ataxia telangiectasia (PMID 9792409; 12552559; 20308662; 21665257; 22649200; 23322442; 23726790; 23807571). This variant has a maximum subpopulation frequency of 0.03% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002285143	SCV005415906	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	PVS1+PM3
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000236583	SCV001955909	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000236583	SCV001963253	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000236583	SCV002037076	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169588	SCV002095367	pathogenic	Ataxia-telangiectasia syndrome	2021-01-19	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551238	SCV004741092	pathogenic	ATM-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The ATM c.1402_1403delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys468Glufs*18). This variant has previously been reported in individuals with autosomal recessive ataxia telangiectasia (Broeks et al. 1998. PubMed ID: 9792409; Lin et al. 2010. PubMed ID: 20308662), breast cancer (Kurian et al. 2014. PubMed ID: 24733792; Aloraifi et al. 2015. PubMed ID: 26094658), and non-polyposis colorectal cancer (Zhang et al. 2015. PubMed ID: 25892863). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140889/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.