Submissions for variant NM_000051.4(ATM):c.8185C>T (p.Gln2729Ter)

dbSNP: rs587781967

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130347	SCV000185198	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	clinical testing	The p.Q2729* pathogenic mutation (also known as c.8185C>T), located in coding exon 55 of the ATM gene, results from a C to T substitution at nucleotide position 8185. This changes the amino acid from a glutamine to a stop codon within coding exon 55. This mutation has been detected in the homozygous state in individuals with ataxia-telangiectasia (Mitui M et al. Hum Mutat, 2003 Jul;22:43-50; Kraus M et al. J Clin Immunol, 2014 Jul;34:561-72). This mutation has also been reported in two unrelated Palestinian women diagnosed with breast cancer at age 39 and 54 (Lolas Hamameh S et al. Int. J. Cancer. 2017 08;141:750-756), one individual with ovarian cancer (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488), and multiple individuals with pancreatic cancer (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390; Hutchings D et al. Mod Pathol, 2019 12;32:1806-1813; Hayashi H et al. Cancer Sci, 2020 Oct;111:3926-3937). 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.
Counsyl	RCV000410300	SCV000486531	likely pathogenic	Ataxia-telangiectasia syndrome	2016-06-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000657613	SCV000779355	pathogenic	not provided	2016-07-07	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.8185C>T at the cDNA level and p.Gln2729Ter (Q2729X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the homozygous state in an individual with classic ataxia-telangiectasia (Mitui 2003). This variant is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410300	SCV000835581	pathogenic	Ataxia-telangiectasia syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2729*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with ataxia-telangiectasia (PMID: 12815592, 24789685). ClinVar contains an entry for this variant (Variation ID: 141726). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130347	SCV000911669	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 56 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 identified in 1/251012 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.
Baylor Genetics	RCV003467141	SCV004209541	pathogenic	Familial cancer of breast	2023-08-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467141	SCV004932904	pathogenic	Familial cancer of breast	2024-02-02	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.	RCV000410300	SCV002079327	pathogenic	Ataxia-telangiectasia syndrome	2020-10-20	no assertion criteria provided	clinical testing