Submissions for variant NM_000051.4(ATM):c.6998C>T (p.Thr2333Ile)

dbSNP: rs150503164

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590099	SCV000149149	uncertain significance	not provided	2025-01-26	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21665257, 23532176, 28843361, 35957908)
Ambry Genetics	RCV000115240	SCV000184909	likely benign	Hereditary cancer-predisposing syndrome	2019-01-14	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	RCV000206376	SCV000259774	likely benign	Ataxia-telangiectasia syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855568	SCV000694340	likely benign	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6998C>T (p.Thr2333Ile) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251024 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.8e-05 vs 0.001), allowing no conclusion about variant significance. However, this variant has also been reported in 6/2559 African American women (i.e. with an allele frequency of 0.0012) who were older than age 70 and cancer free (FLOSSIES database), supporting a benign role for the variant. The variant, c.6998C>T, has been reported in the literature in an individuals affected with Lung adenocarcinoma or breast/ovarian cancer (Parry_2017, Gifoni_2022). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer or 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: 35957908, 28843361). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=3), likely benign (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000115240	SCV000910903	likely benign	Hereditary cancer-predisposing syndrome	2016-04-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000855568	SCV002518024	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115240	SCV002536853	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000855568	SCV002774772	likely benign	not specified	2024-11-22	criteria provided, single submitter	clinical testing	***only use if reclassification to LB is not approved*** The ATM c.6998C>T (p.Thr2333Ile) variant has been reported in the published literature in individuals with lung adenocarcinoma (PMID: 28843361 (2017)) and breast cancer (PMID: 35957908 (2022)). The frequency of this variant in the general population, 0.00084 (21/24960 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.	RCV004589574	SCV005085815	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].
PreventionGenetics, part of Exact Sciences	RCV004549568	SCV004743821	likely benign	ATM-related disorder	2023-07-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).