Submissions for variant NM_000051.4(ATM):c.4060C>A (p.Pro1354Thr)

gnomAD frequency: 0.00019  dbSNP: rs145119475

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656759	SCV000149093	uncertain significance	not provided	2023-04-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 28779002, 33280026, 34299313, 20305132, 21787400, 26689913, 29522266, 30262796, 29684080, 28652578, 27913932, 31658756, 32854451, 35047863)
Ambry Genetics	RCV000115184	SCV000185799	likely benign	Hereditary cancer-predisposing syndrome	2021-03-23	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.
Invitae	RCV000168271	SCV000218943	benign	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000193232	SCV000246617	uncertain significance	not specified	2015-01-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003389684	SCV000805552	uncertain significance	ATM-related condition	2023-12-27	criteria provided, single submitter	clinical testing	The ATM c.4060C>A variant is predicted to result in the amino acid substitution p.Pro1354Thr. This variant has been reported in individuals with a personal history of cancer (Lu et al. 2015. PubMed ID: 26689913, supplementary data 12) and has also been reported in an equal numbers of breast cancer cases and controls (Tavtigian et al. 2009. Table S2. PubMed ID: 19781682). In two other large cancer cohort studies, this variant was reported as a variant of uncertain significance (Quezada Urban et al. 2018. PubMed ID: 30262796, Supplementary Table 2; Fanale et al. 2020. PubMed ID: 32854451). It has been reported at frequencies up to ~0.04% in a large population database and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127379/). Although we suspect that this variant could be benign, at this time, its clinical significance is classified as uncertain due to the absence of conclusive functional and genetic evidence.
Mendelics	RCV003492456	SCV000838531	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115184	SCV000902664	likely benign	Hereditary cancer-predisposing syndrome	2015-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193232	SCV000918509	likely benign	not specified	2023-04-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4060C>A (p.Pro1354Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 248752 control chromosomes, predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00019 vs 0.001), allowing no conclusion about variant significance. However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in Southern Europeans 0.0012 (14/11412 alleles), suggesting that the variant could be a benign polymorphism. In addition, the variant was reported in 6/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). c.4060C>A has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes, but was also repeatedly found in controls or non-cancer-related patient cohorts (e.g. Tavtigian_2009, Bernstein_2010, Tavera-Tapia_2017, Tiao_2017, Quezada Urban_2018, Urbina-Jara_2019, Kraemer_2019, Fanale_2020, Dorling_2021, Guglielmi_2021, Yu_2022), providing no strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as VUS (n=9), likely benign (n=3)/benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000656759	SCV001249803	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	ATM: PM2, BP4
Illumina Laboratory Services, Illumina	RCV000168271	SCV001262665	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656759	SCV001469349	uncertain significance	not provided	2019-10-17	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000656759	SCV001474794	likely benign	not provided	2022-06-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656759	SCV001713574	uncertain significance	not provided	2020-11-25	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000115184	SCV001911459	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.4060C>A (p.Pro1354Thr) variant has an allele frequency of 0.00018 (0.002%, 48/ 265,608 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00038 (0.04%, 44/115,626 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. Also, this missense variant does not alter the protein function / structure on the in-silico prediction reports of REVEL and Vest4 (BP4). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 (PMID: 33280026).
Sema4, Sema4	RCV000115184	SCV002528952	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115184	SCV004228125	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354169	SCV001548713	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Pro1354Thr variant was identified in a large-scale case control study in 1 of 5062 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer and was present in 1 of 4490 control chromosomes (frequency: 0.0002) from healthy individuals (Tavtigian-2009). The variant was identified in dbSNP (ID: rs145119475) as “With Uncertain significance” allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and University of Chicago). The variant was not identified in Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 50 of 274452 chromosomes at a frequency of 0.0002 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017) including 45 of 124128 European chromosomes and 1 of 6442 “other” chromosomes. The p.Pro1354Thr residue is not conserved in mammals, the threonine amino acid is found in mouse, African clawed frog, and zebrafish; and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000656759	SCV001928344	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656759	SCV001956372	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656759	SCV001966552	likely benign	not provided		no assertion criteria provided	clinical testing