Submissions for variant NM_000051.4(ATM):c.3049C>T (p.Gln1017Ter)

dbSNP: rs730881388

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211992	SCV000209780	pathogenic	not provided	2023-11-13	criteria provided, single submitter	clinical testing	Nonsense 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; Observed with an ATM missense variant in a patient with atypical ataxia telangiectasia, and patient-derived cell line demonstrated reduced ATM protein and impaired phosphorylation of downstream targets (PMID: 31050087); 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); Observed in individuals with a personal or family history of breast cancer (PMID: 29308099, 34377931); This variant is associated with the following publications: (PMID: 29308099, 26681312, 34377931, 31447099, 31050087)
Ambry Genetics	RCV000159761	SCV000216002	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	clinical testing	The p.Q1017* pathogenic mutation (also known as c.3049C>T), located in coding exon 19 of the ATM gene, results from a C to T substitution at nucleotide position 3049. This changes the amino acid from a glutamine to a stop codon within coding exon 19. This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000457084	SCV000546762	pathogenic	Ataxia-telangiectasia syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1017*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 181992). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000457084	SCV000694246	pathogenic	Ataxia-telangiectasia syndrome	2019-10-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3049C>T (p.Gln1017X) 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 (e.g. c.3085dupA (p.Thr1029fsX19), c.3245_3247delinsTGAT (p.His1082fsX14), c.3372C>G (p.Tyr1124X)). The variant was absent in 251048 control chromosomes (gnomAD). c.3049C>T has been reported in the literature in an individual affected with Breast Cancer (Susswein_2016).To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258064	SCV001434895	likely pathogenic	Ataxia-telangiectasia syndrome; Breast cancer, susceptibility to	2018-10-08	criteria provided, single submitter	clinical testing	The c.3049C>T (p.Gln1017*) variant in the ATM gene is predicted to introduce a premature translation termination codon. This variant has not been reported in the gnomAD database. Therefore, the c.3049C>T (p.Gln1017*) variant in the ATM gene is classified as likely pathogenic.
Sema4, Sema4	RCV000159761	SCV002535289	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-11	criteria provided, single submitter	curation
Baylor Genetics	RCV003467240	SCV004210128	pathogenic	Familial cancer of breast	2023-11-21	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003467240	SCV004244527	pathogenic	Familial cancer of breast	2023-12-04	criteria provided, single submitter	clinical testing	PVS1, PS4_Supporting, PM2
Myriad Genetics, Inc.	RCV003467240	SCV004931380	pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.