Submissions for variant NM_000051.4(ATM):c.1120C>T (p.Gln374Ter)

dbSNP: rs1185204988

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668668	SCV000793306	likely pathogenic	Ataxia-telangiectasia syndrome	2017-08-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762812	SCV000893170	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000668668	SCV000937702	pathogenic	Ataxia-telangiectasia syndrome	2023-07-31	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553261). This premature translational stop signal has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 9682216, 10425038). This sequence change creates a premature translational stop signal (p.Gln374*) 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).
Color Diagnostics, LLC DBA Color Health	RCV001185328	SCV001351523	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia cancer in the literature and is considered a founder in the Costa Rican population (PMID 9682216, 10425038). 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. Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001185328	SCV002746004	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	The p.Q374* pathogenic mutation (also known as c.1120C>T), located in coding exon 8 of the ATM gene, results from a C to T substitution at nucleotide position 1120. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been described as a Costa Rican founder mutation that has been observed in multiple ataxia-telangiectasia patients (Telatar M et al. Mol. Genet. Metab., 1998 May;64:36-43). This mutation has also been reported in conjunction with deletion of chromosome 11q in patients with chronic lymphocytic leukemia (Austen B et al. J. Clin. Oncol., 2007 Dec;25:5448-57; Skowronska A et al. Haematologica, 2012 Jan;97:142-6). 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.
Myriad Genetics, Inc.	RCV004026101	SCV004931294	pathogenic	Familial cancer of breast	2024-01-12	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.