ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4709T>C (p.Val1570Ala) (rs140856217)

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Total submissions: 14
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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 2019-12-31 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
Integrated Genetics/Laboratory Corporation of America RCV000212021 SCV000694289 uncertain significance not specified 2019-02-19 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 277282 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than expected for a pathogenic variant in ATM causing Breast Cancer (0.00072 vs 0.001), allowing no conclusion about variant significance. However, the variant was reported to be found in the FLOSSIES database in 12/7325 European American women, who were older than age 70 years and have never had cancer. The frequency in this cohort is higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0016 vs. 0.001), suggesting a benign role for the variant. c.4709T>C has been reported in the literature in individuals affected with various cancer phenotypes (Hauke 2018, Mandelker 2017, Shindo 2017, Yadav 2016, Haiman 2015, Yurgelun 2015, Bernstein 2010, Pugh 2009, Dork 2001, Izatt 1999), however in most of the cases co-occurrence and/or co-segregation data was not provided, therefore these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One recent study reported the variant to be found in 3 cases with CLL, and calculated an OR of 2.26 compared to controls. However this analysis had a relatively small sample size and most patients were sporadic cases, thus this risk association might not be reliable (Tiao 2017). A co-occurrence with another pathogenic variant has been reported in our internal database (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. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (5x) and as likely benign (3x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000122851 SCV000743729 likely benign Ataxia-telangiectasia syndrome 2014-10-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,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 RCV000115199 SCV000902602 benign Hereditary cancer-predisposing syndrome 2016-08-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586056 SCV001148426 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Neoplasm of ovary; Breast carcinoma 2020-01-27 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in heterozygous state.

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