Submissions for variant NM_000051.4(ATM):c.7004C>T (p.Thr2335Ile)

gnomAD frequency: 0.00029  dbSNP: rs3092831

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166521	SCV000217321	likely benign	Hereditary cancer-predisposing syndrome	2020-06-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168468	SCV000219168	likely benign	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000586878	SCV000292479	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, hematological malignancy, or pancreatic cancer (PMID: 33850299, 23555315, 35047863); This variant is associated with the following publications: (PMID: 26787654, 25530832, 33850299, 23555315, 35047863, 23532176)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855628	SCV000694341	uncertain significance	not specified	2024-04-30	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7004C>T (p.Thr2335Ile) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 1613966 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.6e-05 vs 0.001), allowing no conclusion about variant significance. c.7004C>T has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast/prostate cancer and/or therapy related myeloid neoplasms (e.g. Young_2015, Haiman_2013, Singhal_2021), while it has also been reported in a pancreatic cancer case (Yu_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23555315, 33850299, 26787654, 35047863). ClinVar contains an entry for this variant (Variation ID: 186867). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000168468	SCV000790698	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166521	SCV000903897	likely benign	Hereditary cancer-predisposing syndrome	2020-03-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000855628	SCV002067105	uncertain significance	not specified	2019-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166521	SCV002536897	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-12	criteria provided, single submitter	curation
Baylor Genetics	RCV003468785	SCV004206248	uncertain significance	Familial cancer of breast	2024-03-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586878	SCV004222081	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00072 (18/24956 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 26787654 (2016) and 23555315 (2013)), pancreatic cancer (PMID: 35047863 (2022)), and hematological malignancies (PMID: 33850299 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV003468785	SCV005084824	likely benign	Familial cancer of breast	2024-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc.	RCV000168468	SCV001458458	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483545	SCV004228648	not provided	Ataxia-telangiectasia syndrome; Hereditary cancer-predisposing syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-18-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004739536	SCV005349501	uncertain significance	ATM-related disorder	2024-06-27	no assertion criteria provided	clinical testing	The ATM c.7004C>T variant is predicted to result in the amino acid substitution p.Thr2335Ile. This variant has been previously reported in individuals with breast cancer, prostate cancer, pancreatic cancer, hematological malignancy, and non-small cell lung cancer (Haiman et al. 2013. PubMed ID: 23555315, Table S6.2; Sosonkina et al. 2014. PubMed ID: 25530832, Table S4; Young et al. 2016. PubMed ID: 26787654, Table S1; Singhal et al. 2021. PubMed ID: 33850299, Table S5; Yu et al. 2022. PubMed ID: 35047863). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186867). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.