Submissions for variant NM_000051.4(ATM):c.6913C>T (p.Gln2305Ter)

dbSNP: rs1282099124

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575199	SCV000668094	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-13	criteria provided, single submitter	clinical testing	The p.Q2305* variant (also known as c.6913C>T), located in coding exon 46 of the ATM gene, results from a C to T substitution at nucleotide position 6913. This changes the amino acid from a glutamine to a stop codon within coding exon 46. This mutation was detected in conjunction with a second mutation in an Italian patient with classic Ataxia-Telangiectasia (Saviozzi S et al. Hum. Mutat., 2003 Apr;21:450). 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	RCV001208902	SCV001380314	pathogenic	Ataxia-telangiectasia syndrome	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2305*) 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 ataxia-telangiectasia (PMID: 12655570). ClinVar contains an entry for this variant (Variation ID: 482710). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798899	SCV002042834	pathogenic	Breast and/or ovarian cancer	2020-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001208902	SCV003934470	pathogenic	Ataxia-telangiectasia syndrome	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6913C>T (p.Gln2305X) 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. The variant was absent in 251316 control chromosomes (gnomAD). c.6913C>T has been reported in the literature in compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Saviozzi_2003, Cavalieri_2008). 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. The following publications have been ascertained in the context of this evaluation (PMID: 17910737, 17124347, 12655570). Three ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV004024500	SCV004933278	pathogenic	Familial cancer of breast	2024-01-30	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.
GeneDx	RCV005250077	SCV005900818	pathogenic	not provided	2024-09-23	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 22927201, 25525159, 12655570, 17124347, 17910737)