ClinVar Miner

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

gnomAD frequency: 0.00045  dbSNP: rs140856217
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Total submissions: 26
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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.
Invitae RCV000122851 SCV000166109 benign Ataxia-telangiectasia syndrome 2021-12-17 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 Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
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 likely benign not specified 2021-09-23 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 Breast Cancer. 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=5; VUS, n=9). 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 re-classified as likely 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
PreventionGenetics,PreventionGenetics RCV000586056 SCV000805570 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing
Mendelics RCV000122851 SCV000838544 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 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
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 Inc 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 RCV001197709 SCV002010812 uncertain significance Familial cancer of breast 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 2021-01-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586056 SCV002047314 likely benign not provided 2020-07-23 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000115199 SCV002527110 likely benign Hereditary cancer-predisposing syndrome 2021-07-21 criteria provided, single submitter curation
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

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