Submissions for variant NM_000051.4(ATM):c.9079dup (p.Ser3027fs)

dbSNP: rs587780645

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122895	SCV000166153	pathogenic	Ataxia-telangiectasia syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the ATM gene (p.Ser3027Lysfs*36). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the ATM protein and extend the protein by 5 additional amino acid residues. This variant is present in population databases (rs587780645, gnomAD 0.003%). This frameshift has been observed in individual(s) with ATM-related conditions (PMID: 15039971, 21965147, 26270727). 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 9080insA, c.9080dupA, and c.9078_9079insA. ClinVar contains an entry for this variant (Variation ID: 135788). This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 19431188, 19691550). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000220797	SCV000273050	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-07	criteria provided, single submitter	clinical testing	The c.9079dupA pathogenic mutation, located in coding exon 62 of the ATM gene, results from a duplication of A at nucleotide position 9079, causing a translational frameshift with a predicted alternate stop codon (p.S3027Kfs*36). This pathogenic mutation has been reported in the literature in a compound heterozygous state with a splice site mutation in a Brazilian patient with classical ataxia telangiectasia (Coutinho G et al. Am. J. Med. Genet. A 2004 Apr;126A(1):33-40). In addition to the clinical data presented in the literature, this frameshift occurs near the 3' terminus of ATM and results in the elongation of the protein by 6 amino acids. This mutation alters the sequence of the FATC domain of the ATM protein which has been shown to be necessary for ATM regulation (Jiang XJ et al. Biol. Chem. 2006 Jun;281(23):15741-6). As such, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000122895	SCV000485608	likely pathogenic	Ataxia-telangiectasia syndrome	2016-09-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000479629	SCV000568344	likely pathogenic	not provided	2018-01-16	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in ATM is denoted c.9079dupA at the cDNA level and p.Ser3027LysfsX36 (S3027KfsX36) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GCTC[dupA]GTGT. The duplication causes a frameshift, which changes a Serine to a Lysine at codon 3027 in the last exon of the gene, and results in an extension of the protein. The last 30 amino acids are replaced by 35 incorrect ones, disrupting the FATC domain (Stracker 2013). ATM Ser3027LysfsX36 has been observed in the compound heterozygous state in individuals with ataxia telangiectasia (Coutinho 2004, Demuth 2011), and in at least one individual with breast cancer (Desmond 2015). Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Mendelics	RCV000122895	SCV001138589	likely pathogenic	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220797	SCV001341249	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-13	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 63 of the ATM gene, creating a frameshift in the last coding exon and extending the length of the ATM protein by 5 amino acids. This variant is expected to alter the FATC domain and disrupt the ATM protein function (PMID: 16603769). This variant has been reported in the compound heterozygous state with a second ATM mutation in individuals affected with ataxia telangiectasia (PMID: 15039971, 21965147). This variant has also been reported in individuals affected with colorectal cancer or hereditary breast and ovarian cancer (PMID: 26270727, 28135145). This variant has been identified in 1/251460 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 Likely Pathogenic.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000220797	SCV001911495	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.9079dup (p.Ser3027Lysfs*36) variant duplicates one nucleotide in the last exon of ATM. It is predicted to create a frame shift and result in an extension of the protein, not triggering nonsense-mediated mRNA decay (NMD). The frame shift after residue 3027 alters the FATC domain, critical for ATM activation as its interaction with the Tip60 histone acetyltransferase allows ATM acetylation and then autophosphorylation (PVS1_Strong, according to the PVS1 algorithm recommended by ACMG/AMP in 2018; PMID: 30192042). This variant appears only once in the gnomAD v2.1.1 non-cancer dataset, specifically in the African subpopulation (PM2; http://gnomad.broadinstitute.org). Moreover, it was detected in two ataxia-telangiectasia probands (PS4_Moderate; PMID: 15039971, 21965147). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1_Strong + PM2 + PS4_Moderate (PMID: 33280026).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122895	SCV002548057	pathogenic	Ataxia-telangiectasia syndrome	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.9079dupA (p.Ser3027LysfsX36) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes. c.9079dupA has been reported in the literature in individuals affected with Ataxia-Telangiectasia and related conditions (example, Coutinho_2004, Demuth_2011, Feliubadal_2021). Seven 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137635	SCV003806832	likely pathogenic	Familial cancer of breast	2022-03-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PS4 supporting, PM2 moderated, PM3 moderated
Baylor Genetics	RCV003137635	SCV004212084	pathogenic	Familial cancer of breast	2023-02-20	criteria provided, single submitter	clinical testing