Submissions for variant NM_000051.4(ATM):c.7000_7003del (p.Tyr2334fs)

dbSNP: rs786203421

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166719	SCV000217530	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	The c.7000_7003delTACA pathogenic mutation, located in coding exon 47 of the ATM gene, results from a deletion of 4 nucleotides at positions 7000 to 7003, causing a translational frameshift with a predicted alternate stop codon (p.Y2334Qfs*4). This alteration was identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375(5):443-53). This alteration was also reported in a woman with breast cancer, melanoma, and a family history of breast cancer (Torrezan GT et al. Front Genet, 2018 May;9:161). 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	RCV000232032	SCV000283031	pathogenic	Ataxia-telangiectasia syndrome	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2334Glnfs*4) 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 (rs763554569, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 27433846). ClinVar contains an entry for this variant (Variation ID: 187035). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000232032	SCV000485465	likely pathogenic	Ataxia-telangiectasia syndrome	2015-12-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166719	SCV000905174	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 48 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 identified in 1/251036 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.
Athena Diagnostics	RCV001657927	SCV001879552	likely pathogenic	not provided	2021-05-11	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).
Revvity Omics, Revvity	RCV000232032	SCV002020815	pathogenic	Ataxia-telangiectasia syndrome	2019-05-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001657927	SCV002522017	pathogenic	not provided	2024-09-12	criteria provided, single submitter	clinical testing	Observed in an individual with an additional ATM variant, phase unknown, with hypersensitivity to ionizing radiation and a range of neurological, developmental, and immunological features (PMID: 34153142); Observed in individuals with a personal and/or family history of melanoma, prostate cancer and/or breast cancer (PMID: 29625052, 26689913, 32832836, 27433846, 36446039); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26689913, 27433846, 29625052, 32832836, 32427313, 29868112, 31658756, 34153142, 29922827, 36451132, 36446039)
Sema4, Sema4	RCV000166719	SCV002536886	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	curation
Baylor Genetics	RCV003468792	SCV004212184	pathogenic	Familial cancer of breast	2024-02-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468792	SCV004931164	pathogenic	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.