Submissions for variant NM_000051.4(ATM):c.4709T>C (p.Val1570Ala)

gnomAD frequency: 0.00046  dbSNP: rs140856217

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586056	SCV000149108	uncertain significance	not provided	2018-01-19	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4709T>C at the cDNA level, p.Val1570Ala (V1570A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant has been reported in several individuals with breast cancer, one with prostate cancer, and at least one with advanced cancer of unspecified type, as well as in an individual with a personal history of a Lynch syndrome-related cancer and/or polyps (Izatt 1999, Dork 2001, Pugh 2009, Tavtigian 2009, Yurgelun 2015, Maxwell, 2016, Tung 2016, Mandelker 2017). In one family, the variant was identified in both a proband with early onset breast cancer and her mother, who also had a history of breast cancer (Izatt 1999). ATM Val1570Ala was observed at an allele frequency of 0.07% (91/126,354) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val1570Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122851	SCV000166109	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115199	SCV000183787	likely benign	Hereditary cancer-predisposing syndrome	2018-09-30	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.
Genetic Services Laboratory, University of Chicago	RCV000212021	SCV000593504	uncertain significance	not specified	2016-10-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212021	SCV000694289	benign	not specified	2022-10-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4709T>C (p.Val1570Ala) 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 0.00041 in 251524 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00041 vs 0.001), allowing no conclusion about variant significance. c.4709T>C has been reported in the literature as a VUS/likely benign variant in settings of multigene panel testing on individuals affected with various cancer phenotypes (e.g. Izatt, 1999, Dork_2001, Gumy-Pause_2006, Bernstein_2010, Haiman_2013, Maxwell_2016, Grasel_2020, Bandeira_2021) without strong evidence for causality. One of these studies reported this variant within settings of loss of heterozygosity (LOH) of the normal allele in a family where it did not clearly segregate with cancer (Grasel_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/ATM-related cancers. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory (BRCA2 c.9097dupA, p.Thr3033fsX11), providing supporting evidence for a benign role. 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. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=7; VUS, n=10). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. At-least one submitter reports a non-specified co-occurrence with mutation in same gene (phase unknown) as a basis of their likely benign classification. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000122851	SCV000743729	likely benign	Ataxia-telangiectasia syndrome	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000122851	SCV000745127	likely benign	Ataxia-telangiectasia syndrome	2017-10-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000122851	SCV000792269	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000122851	SCV000838544	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115199	SCV000902602	benign	Hereditary cancer-predisposing syndrome	2016-08-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586056	SCV001148426	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ATM: PM2, BP4
Illumina Laboratory Services, Illumina	RCV000122851	SCV001264585	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197709	SCV001368488	uncertain significance	Familial cancer of breast	2020-01-27	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000586056	SCV001713576	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000212021	SCV001879481	likely benign	not specified	2021-05-07	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000586056	SCV002010812	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798317	SCV002042241	uncertain significance	Breast and/or ovarian cancer	2023-05-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586056	SCV002047314	likely benign	not provided	2022-06-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115199	SCV002527110	likely benign	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212021	SCV002760573	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000122851	SCV003827481	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-23	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115199	SCV005045390	benign	Hereditary cancer-predisposing syndrome	2024-05-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001197709	SCV005084026	likely benign	Familial cancer of breast	2024-05-20	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	RCV004549555	SCV000805570	uncertain significance	ATM-related disorder	2024-08-20	no assertion criteria provided	clinical testing	The ATM c.4709T>C variant is predicted to result in the amino acid substitution p.Val1570Ala. This variant has been reported in at least one study to segregate with breast cancer in a first-degree relative of the proband (Table 3, Izatt et al. 1999. PubMed ID: 10534763). It has also been reported in several individuals with a history of breast cancer (Dörk et al. 2001. PubMed ID: 11606401; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Tung et al. 2016. PubMed ID: 26976419), as well as in an individual with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754), but was classified as a variant of uncertain significance. It was also found as a recurring variant in patients with chronic lymphocytic leukemia (Tiao et al. 2017. PubMed ID: 28652578) as well as in individuals with pancreatic ductal adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) 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/127394/). At this time, we classify the clinical significance of this variant as uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354496	SCV001549128	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Val1570Ala variant was identified in 7 of 12586 proband chromosomes (frequency: 0.0005) from U.S., Canadian, German and British individuals or families with breast cancer, Lynch syndrome or prostate cancer and was not identified in 4998 control chromosomes from healthy individuals (Tavtigian 2009, Tung 2016, Izzat 2009, Dork 2001, Yurgelin 2015, Pugh 2009). The variant was also identified in dbSNP (ID: rs140856217) as “With Uncertain significance allele”, ClinVar and Clinvitae (1x classified as likely benign by Ambry Genetics, 2x uncertain significance by GeneDx and Invitae). The variant was not identified in the COGR, COSMIC, MutDB, or the LOVD 3.0 databases. The variant was identified in control databases in 112 of 276738 chromosomes at a frequency of 0.0004 in the following populations: European non-Finnish 91 of 126354 chromosomes (freq. 0.0007); “Other” in 3 of 6464 chromosomes (freq. 0.0005); Latino in 15 of 34400 chromosomes (freq. 0.0004); European Finnish in 2 of 25720 chromosomes (freq. 0.00008); African in 1 of 24028 chromosomes (freq. 0.00004) (Genome Aggregation Consortium Feb 27, 2017). This variant was found in one British individual with: two separate primary early-onset breast cancers, segregation with one family member with breast cancer (mother), loss of heterozygosity for ATM and neighbouring loci in tumour DNA, and sensitivity reaction to radiotherapy, however the authors conclude that this may represent a rare polymorphism because the residue is not conserved in mouse and they did not perceive that the variant was found in a functional domain (Izzat 2009). The p.Val1570Ala residue is not conserved in mammals and 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000586056	SCV001744578	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586056	SCV001807860	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000586056	SCV001906185	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000586056	SCV001919560	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586056	SCV001958328	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000586056	SCV002036114	likely benign	not provided		no assertion criteria provided	clinical testing