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

dbSNP: rs754562056

Total submissions: 9

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	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 370611). 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). This variant is present in population databases (rs754562056, gnomAD 0.0009%). 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).
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	2024-12-26	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.
NHS Central & South Genomic Laboratory Hub	RCV005252871	SCV005907149	pathogenic	Inherited breast cancer and ovarian cancer	2025-04-09	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005355688	SCV005912536	pathogenic	ATM-related cancer predisposition	2022-01-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002348124	SCV006061483	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-05	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 37/63 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 24549055, 28087566, 28779002, 32802943). This variant has been identified in 1/250986 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.