Submissions for variant NM_000051.4(ATM):c.4804_4805del (p.Val1602fs)

dbSNP: rs864622290

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205765	SCV000259990	pathogenic	Ataxia-telangiectasia syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1602Leufs*2) 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 (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 219873). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000217555	SCV000277452	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-23	criteria provided, single submitter	clinical testing	The c.4804_4805delGT pathogenic mutation, located in coding exon 31 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 4804 to 4805, causing a translational frameshift with a predicted alternate stop codon (p.V1602Lfs*2). 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	RCV001559574	SCV001781828	pathogenic	not provided	2022-08-15	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 individuals with breast cancer in published literature (Lu et al., 2019; Palmer et al., 2020; Haverfield et al., 2021); This variant is associated with the following publications: (PMID: 34404389, 30128536, 32427313)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000205765	SCV002074523	pathogenic	Ataxia-telangiectasia syndrome	2022-01-02	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4804_4805delGT (p.Val1602LeufsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and reported with an associated phenotype of Ataxia Telangiectasia in the HGMD database. The variant was absent in 251276 control chromosomes. To our knowledge, c.4804_4805delGT has not been reported in the literature in individuals affected with Ataxia-Telangiectasia, but has been reported in the literature as a pathogenic variant identified in individuals with breast cancer and within a multi center cohort study of physician-directed genetic screening to evaluate personal risk for medically actionable disorders (example, Lu_2019, Palmer_2020, Haverfield_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002500645	SCV002811707	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-03-31	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003233496	SCV003932302	likely pathogenic	ATM-related disorder	2023-02-07	criteria provided, single submitter	clinical testing	PVS1, PM2
Baylor Genetics	RCV003468939	SCV004211997	likely pathogenic	Familial cancer of breast	2023-11-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468939	SCV004930601	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.