Submissions for variant NM_000051.4(ATM):c.5554C>T (p.Gln1852Ter)

dbSNP: rs754562056

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409717	SCV000485972	likely pathogenic	Ataxia-telangiectasia syndrome	2016-03-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409717	SCV001401485	pathogenic	Ataxia-telangiectasia syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1852*) 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 (rs754562056, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 24549055, 28779002). ClinVar contains an entry for this variant (Variation ID: 370611). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002272217	SCV002556443	likely pathogenic	Familial cancer of breast	2022-05-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002348124	SCV002649961	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The p.Q1852* pathogenic mutation (also known as c.5554C>T), located in coding exon 36 of the ATM gene, results from a C to T substitution at nucleotide position 5554. This changes the amino acid from a glutamine to a stop codon within coding exon 36. This alteration has been identified in a cohort of high-risk breast/ovarian cancer patients and has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Decker B et al. J. Med. Genet. 2017 11;54:732-741). This alteration was also reported as an actionable incidental pathological finding in an individual with a family history of female breast and pancreatic cancer and brain tumor from a cohort of 200 individuals with cardiovascular disease undergoing whole exome sequencing (Seidelmann SB et al. Circ Cardiovasc Genet. 2017 Feb;10:). In addition to the information 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.
Baylor Genetics	RCV002272217	SCV004210236	pathogenic	Familial cancer of breast	2023-06-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002272217	SCV004930350	pathogenic	Familial cancer of breast	2024-01-25	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.