Submissions for variant NM_000051.4(ATM):c.9091C>T (p.Gln3031Ter)

dbSNP: rs2091249987

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179145	SCV001343753	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 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 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 Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192363	SCV001360417	likely pathogenic	Familial cancer of breast	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: ATM c.9091C>T (p.Gln3031X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. There have not been any truncations downstream of this variant in our database that have been classified as pathogenic. The variant was absent in 251428 control chromosomes. c.9091C>T has been reported in the literature in an individual with a family history of breast cancer (Li_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001247349	SCV001420764	pathogenic	Ataxia-telangiectasia syndrome	2020-07-24	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with breast cancer (PMID: 29752822). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the ATM gene (p.Gln3031*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acids of the ATM protein. This variant disrupts the C-terminus of the ATM protein. Other variant(s) that disrupt this region (p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 19691550, 18560558, 10980530, 26628246, 19431188). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001179145	SCV002682843	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-04	criteria provided, single submitter	clinical testing	The p.Q3031* pathogenic mutation (also known as c.9091C>T), located in coding exon 62 of the ATM gene, results from a C to T substitution at nucleotide position 9091. This changes the amino acid from a glutamine to a stop codon within coding exon 62. This alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 26 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in one breast cancer patient in China (Li JY et al. Int J Cancer. 2019 01;144:281-289). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV001192363	SCV004930353	pathogenic	Familial cancer of breast	2024-02-06	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.