Submissions for variant NM_000051.4(ATM):c.1215del (p.Asn405fs)

dbSNP: rs1555069815

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000576782	SCV000678173	likely pathogenic	Ataxia-telangiectasia syndrome	2017-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000657201	SCV000778927	pathogenic	not provided	2020-10-08	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; Not observed in large population cohorts (Lek 2016); Observed in individuals with a personal or family history including breast cancer (Couch 2015, Fostira 2018); Observed in a patient with ataxia telangiectasia who carried a second ATM variant, phase not determined, and who had very low ATM protein levels (Nahas 2009); This variant is associated with the following publications: (PMID: 16387360, 25452441, 19147735, 29335925, 32885271)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659279	SCV000781079	pathogenic	Familial cancer of breast	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576782	SCV000825167	pathogenic	Ataxia-telangiectasia syndrome	2023-09-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn405Lysfs*15) 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 487449). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 16387360, 25452441). This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health	RCV000771728	SCV000904385	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 9 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 individuals affected with breast cancer (PMID: 25452441, 29335925). This variant has not been identified 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.
Ambry Genetics	RCV000771728	SCV001170511	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-18	criteria provided, single submitter	clinical testing	The c.1215delT pathogenic mutation, located in coding exon 8 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 1215, causing a translational frameshift with a predicted alternate stop codon (p.N405Kfs*15). This mutation has been reported in both female and male breast cancer cohorts, and in a proband with mantle cell lymphoma who had three siblings with ataxia-telangiectasia (compound heterozygous with another ATM mutation) (Briani C et al. Leuk. Res. 2006 Sep;30(9):1193-6; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169(1):105-113). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000576782	SCV002557631	pathogenic	Ataxia-telangiectasia syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (AT; MIM#208900) and cancer susceptibility (MIM#114480). (I) 0106 - This gene is associated with autosomal recessive ataxia-telangiectasia. However, heterozygous carriers of specific pathogenic variants have an increased risk of breast cancer (PMID: 27595995). Germline variants in this gene may also contribute to increased risk of other cancers including gastic, colorectal, and pancreatic cancers, however the risk is not well established at this stage (PMID: 22585167, 27978560, 26506520). (I) 0115 - Variants in this gene are known to have variable expressivity with regard to ataxia-telangiectasia. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic or pathogenic, and reported in heterozygous individuals with breast cancer, or compound heterozygous individuals with ataxia-telangiectasia (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000659279	SCV004216240	pathogenic	Familial cancer of breast	2021-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000659279	SCV004931352	pathogenic	Familial cancer of breast	2024-01-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000657201	SCV005199602	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356119	SCV001551192	likely pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asn405LysfsX15 variant was identified in the literature in a 52-year-old woman presented with a mild tremor on her left hand (symptoms suggestive of A-T were not present) and in the patient’s 96-year old healthy father (Briani 2005). The variant was identified in ClinVar (classified as likely pathogenic by Counsyl), and Clinvitae. The variant was not identified in dbSNP, COGR, Cosmic, LOVD 3.0, or ATM-LOVD databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Asn405LysfsX15 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 405 and leads to a premature stop codon at position 419. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Natera, Inc.	RCV000576782	SCV002092801	pathogenic	Ataxia-telangiectasia syndrome	2021-01-29	no assertion criteria provided	clinical testing