Submissions for variant NM_000051.4(ATM):c.8655dup (p.Val2886fs)

dbSNP: rs753961188

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486055	SCV000569631	pathogenic	not provided	2019-01-09	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in ATM is denoted c.8655dupT at the cDNA level and p.Val2886CysfsX10 (V2886CfsX10) at the protein level. The normal sequence, with the base that is duplicated in brackets, is AACT[dupT]GTAC. The duplication causes a frameshift which changes a Valine to a Cysteine at codon 2886, and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.8655dupT, also described as c.8653_8654insT using alternate nomenclature, has been reported in the compound heterozygous state with an ATM nonsense variant in a child with clinical features of Ataxia-telangiectasia (Barbaro 2017). Based on currently available evidence, we consider this to be a pathogenic variant.
Ambry Genetics	RCV000569773	SCV000672647	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	clinical testing	The c.8655dupT pathogenic mutation, located in coding exon 58 of the ATM gene, results from a duplication of T at nucleotide position 8655, causing a translational frameshift with a predicted alternate stop codon (p.V2886Cfs*10). This alteration has been identified in individuals diagnosed with pancreatic, thyroid, kidney, breast and prostate cancers (Hu C et al. JAMA, 2018 06;319:2401-2409; Hartman TR et al. Sci Rep, 2020 08;10:13518; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Color Diagnostics, LLC DBA Color Health	RCV000569773	SCV000682508	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-12	criteria provided, single submitter	clinical testing	This variant (also known as c.8653_8654insT) inserts 1 nucleotide in exon 59 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 a child affected with autosomal recessive ataxia-telangiectasia in compound heterozygous state with other pathogenic variant (PMID: 27873105), indicating that this variant contributes to disease.This variant has been identified in 5/250320 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690610	SCV000818306	pathogenic	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val2886Cysfs*10) 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 (rs753961188, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 27873105). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.8653_8654insT. ClinVar contains an entry for this variant (Variation ID: 420694). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000690610	SCV001163275	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000486055	SCV001449954	pathogenic	not provided	2019-03-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798858	SCV002042322	pathogenic	Breast and/or ovarian cancer	2020-01-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000486055	SCV004024337	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003155946	SCV004212063	pathogenic	Familial cancer of breast	2023-03-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003155946	SCV004933563	pathogenic	Familial cancer of breast	2024-02-05	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	RCV000486055	SCV005199625	pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005044719	SCV005680946	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-03-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354733	SCV001549420	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Val2886Cysfs*10 variant was identified in the literature in a compound heterozygous state in a child affected with ataxia-telangiectasia (Barbaro 2016). The variant was also identified in dbSNP (ID: rs753961188) as "With Pathogenic allele" and ClinVar (classified as pathogenic by Invitae, Color and Ambry Genetics; and as likely pathogenic by GeneDx). The variant was not identified in the LOVD 3.0 database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.8655dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2886 and leads to a premature stop codon at position 2895. 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, this variant meets our laboratory’s criteria to be classified as pathogenic.
BRCAlab, Lund University	RCV003155946	SCV002589044	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing