Submissions for variant NM_000051.4(ATM):c.3511C>T (p.Gln1171Ter)

dbSNP: rs876659067

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213580	SCV000275072	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	The p.Q1171* pathogenic mutation (also known as c.3511C>T), located in coding exon 23 of the ATM gene, results from a C to T substitution at nucleotide position 3511. This changes the amino acid from a glutamine to a stop codon within coding exon 23. This mutation was observed in a cohort of 8085 unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res. 2017 Jul;doi: 10.1158/1078-0432.CCR-16-3227. [Epub ahead of print]). It was also reported in conjunction with another ATM alteration in an individual with ataxia telangiectasia, resulting in decreased expression of ATM protein and increased radiosensitivity measured by a cell colony survival assay (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun; 70(2):122-33). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000802075	SCV000941889	pathogenic	Ataxia-telangiectasia syndrome	2023-08-06	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1171*) 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 premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 10873394, 22071889, 28724667). 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 disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 231278).
Color Diagnostics, LLC DBA Color Health	RCV000213580	SCV004359793	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 24 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant reduced ATM protein expression, increased alpha-fetoprotein, and resulted in radiosensitivity (PMID: 10873394, 22071889). This variant has been reported in the compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 10873394, 22071889). This variant has also been reported in individuals affected with breast cancer (PMID: 28724667, 30607632, 33471991) and high-grade serous ovarian cancer (PMID: 36000185). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV003155932	SCV004933259	pathogenic	Familial cancer of breast	2024-01-22	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.	RCV000802075	SCV001457150	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV003155932	SCV002588833	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing