Submissions for variant NM_000051.4(ATM):c.2554C>T (p.Gln852Ter)

gnomAD frequency: 0.00003  dbSNP: rs758081262

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457787	SCV000546653	pathogenic	Ataxia-telangiectasia syndrome	2023-09-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln852*) 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 (rs758081262, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with ataxia telangiectasia (PMID: 22130802, 24172824, 26098866, 28825054). ClinVar contains an entry for this variant (Variation ID: 407450). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762819	SCV000893177	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001015914	SCV001176806	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-09	criteria provided, single submitter	clinical testing	The p.Q852* pathogenic mutation (also known as c.2554C>T), located in coding exon 16 of the ATM gene, results from a C to T substitution at nucleotide position 2554. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This mutation has been reported in a homozygous state in a patient with ataxia telangiectasia (Driessen GJ et al. J. Allergy Clin. Immunol. 2013 May;131(5):1367-75.e9). It has also been reported in the heterozygous state in probands with gastric cancer, prostate cancer, and chronic lymphocytic leukemia (Helgason H et al. Nat. Genet. 2015 Aug;47(8):906-10; Abida W et al. JCO Precis Oncol. 2017 Jul;2017; Navrkalova V et al. Haematologica 2016 09;101(9):e369-73). In addition to the clinical data published 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.
Color Diagnostics, LLC DBA Color Health	RCV001015914	SCV001348268	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 17 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 the homozygous state and the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 22130802, 23566627, 26098866, 28126470). This variant has also been reported in an individual affected with prostate cancer (PMID: 32183364). One study has shown that this variant is associated with an increased risk of gastric cancer in Iceland (OR = 4.74; 95% CI 3.03-7.40)(PMID: 26098866). This variant has been identified in 4/282786 chromosomes 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.
Sema4, Sema4	RCV001015914	SCV002532290	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-08	criteria provided, single submitter	curation
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000457787	SCV004239255	pathogenic	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003155940	SCV004933168	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.
Natera, Inc.	RCV000457787	SCV001462077	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV003155940	SCV002588811	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003168780	SCV002758086	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research