Submissions for variant NM_000051.4(ATM):c.4741dup (p.Ile1581fs)

dbSNP: rs864622164

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543529	SCV000259526	pathogenic	Ataxia-telangiectasia syndrome	2023-09-11	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: 453535). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 24951259). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile1581Asnfs*5) 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).
Ambry Genetics	RCV000561093	SCV000665183	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-06	criteria provided, single submitter	clinical testing	The c.4741dupA pathogenic mutation, located in coding exon 30 of the ATM gene, results from a duplication of A at nucleotide position 4741, causing a translational frameshift with a predicted alternate stop codon (p.I1581Nfs*5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000657386	SCV000779119	pathogenic	not provided	2017-10-11	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in ATM is denoted c.4741dupA at the cDNA level and p.Ile1581AsnfsX5 (I1581NfsX5) at the protein level. Using alternate nomenclature, this variant has previously been reported as ATM c.47356_4736insA. The normal sequence, with the base that is duplicated in brackets, is CAAAAA[dupA]TCAA. The duplication causes a frameshift which changes an Isoleucine to an Asparagine at codon 1581, and creates a premature stop codon at position 5 of the new reading frame. Although this variant has not, to our knowledge, been reported as a germline variant, it has been reported as a somatic variant in a colorectal tumor (Yu 2015). Based on current evidence, we consider this variant to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000561093	SCV000904614	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-20	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 31 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657386	SCV001713577	likely pathogenic	not provided	2020-04-17	criteria provided, single submitter	clinical testing	PVS1, PM2
MGZ Medical Genetics Center	RCV000543529	SCV002579996	pathogenic	Ataxia-telangiectasia syndrome	2021-11-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004023646	SCV004933459	pathogenic	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV004023646	SCV005056906	pathogenic	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing