Submissions for variant NM_000051.4(ATM):c.7313C>T (p.Thr2438Ile)

gnomAD frequency: 0.00056  dbSNP: rs147604227

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589408	SCV000149155	likely benign	not provided	2021-03-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17333338, 23274167, 33309985, 22529920, 8808599, 25503501, 10817650, 25980754, 19781682, 28779002, 23555315, 21933854, 30287823, 33095795)
Ambry Genetics	RCV000115246	SCV000186496	likely benign	Hereditary cancer-predisposing syndrome	2019-02-11	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	RCV000200256	SCV000254142	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115246	SCV000576463	uncertain significance	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515201	SCV000611370	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260260	SCV000694348	likely benign	not specified	2024-07-25	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7313C>T (p.Thr2438Ile) 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 0.00014 in 298578 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.7313C>T has been reported in the literature in sequencing studies of individuals with varied indications such as, an individual with Ataxia Telangiectasia (Li_2000), as not associated with risk of breast cancer in an array GWAS study of a multiethnic population (Haiman_2013), unaffected controls of African American and Japanese ancestry (Hirsch_2008, Momozawa_2018), a patient with a clinical indication of Lynch syndrome associated cancer and/or polyps undergoing multigene panel testing (Yurgelun_2015), and a patient with AML in the TGCA cohort (Lu_2015). Furthermore, the variant has been reported in a cerebellar ataxia patient (Coutelier_2018), breast cancer cases and controls (Weitzel_2019, Eygelaar_2022, Guindalini_2022), a patient with primary ovarian insufficiency (Franca_2020), in PDAC patients (Zimmermann_2021) and in Hepatic cancer cases and controls (Okawa_2023). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. Additionally, the variant was found to occur in ten African American women who are older than 70 years of age and cancer free as reported in the FLOSSIES database. 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: 29482223, 35039564, 33095795, 33309985, 35264596, 23555315, 17333338, 10817650, 26689913, 25503501, 30287823, 36243179, 21933854, 31206626, 33421217, 25980754, 33747920). ClinVar contains an entry for this variant (Variation ID: 127440). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000200256	SCV000838591	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000589408	SCV000861415	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115246	SCV000902700	benign	Hereditary cancer-predisposing syndrome	2015-09-08	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225326	SCV002504765	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115246	SCV002537420	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-11	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589408	SCV004222117	likely benign	not provided	2023-09-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589575	SCV005085826	likely benign	Familial cancer of breast	2024-06-13	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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354272	SCV001548846	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Thr2438Ile variant was identified in 6 of 43,426 proband chromosomes (frequency: 0.0001) from individuals or families with ataxia telangiectasia, Lynch Syndrome, or breast cancer and was present in 4 of 58,628 control chromosomes (frequency: 0.00006) from healthy individuals (Momozawa 2018, Hirsch 2008, Decker 2017, Yurgelun 2015, Maxwell 2015). The variant was identified in dbSNP (rs147604227) as “with uncertain significance, other allele”, ClinVar (classified as uncertain significance by Integrated Genetics, GeneDx, Eurofins and 3 other submitters; as likely benign by Invitae and Ambry Genetics; and as benign by Color) and LOVD 3.0 (observed 3x). The variant was identified in control databases in 55 of 282,330 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 50 of 24,936 chromosomes (freq: 0.002) and Latino in 5 of 35,420 chromosomes (freq: 0.0001), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The variant was observed in an ataxia telangiectasia patient in cis with a pathogenic ATM variant (Li 2000), decreasing the likelihood that this variant has clinical significance. The p.Thr2438 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004549569	SCV004114792	uncertain significance	ATM-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The ATM c.7313C>T variant is predicted to result in the amino acid substitution p.Thr2438Ile. This variant has been reported in an individual with ataxia telangiectasia but appeared to be in cis with a truncating variant (Li and Swift. 2000. PubMed ID: 10817650). This variant has been reported in an individual with suspected Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754, Supplemental table 2). One study reported that this variant is not associated with breast cancer (Haiman et al. 2013. PubMed ID: 23555315, Table S6). it has also been observed in three individuals with breast cancer (Table S3, Guindalini et al. 2022. PubMed ID: 35264596) and found in a control individual from a breast cancer study (Hirsch et al. 2008. PubMed ID: 17333338). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127440/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.