Submissions for variant NM_000051.4(ATM):c.3880dup (p.Ile1294fs)

dbSNP: rs1057516541

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410605	SCV000485847	likely pathogenic	Ataxia-telangiectasia syndrome	2016-02-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569268	SCV000668150	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	The c.3880dupA pathogenic mutation, located in coding exon 25 of the ATM gene, results from a duplication of A at nucleotide position 3880, causing a translational frameshift with a predicted alternate stop codon (p.I1294Nfs*8). This mutation (designated as c.3880insA) was reported in conjunction with another truncating ATM mutation in a patient with ataxia-telangiectasia. Cell lines derived from this individual demonstrated absence of ATM protein expression (Keimling M et al. FASEB J. 2011 Nov;25(11):3849-60). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410605	SCV000937930	pathogenic	Ataxia-telangiectasia syndrome	2022-02-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370505). This variant is also known as c.3880fs. This premature translational stop signal has been observed in individual(s) with ataxia telangiectasia (PMID: 21778326). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile1294Asnfs*8) 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).
GeneDx	RCV002472999	SCV002770332	pathogenic	not provided	2022-06-20	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 at significant frequency in large population cohorts (gnomAD); Observed in the apparent compound heterozygous state in individuals with ataxia-telangiectasia (Keimling 2011); This variant is associated with the following publications: (PMID: 21778326)
Color Diagnostics, LLC DBA Color Health	RCV000569268	SCV004360003	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 26 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 an individual affected with ataxia telangiectasia in compound heterozygous state with another truncating variant in the same gene (PMID: 21778326). 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.
Myriad Genetics, Inc.	RCV004022137	SCV004932954	pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.