ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.610G>A (p.Gly204Arg) (rs147915571)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235097 SCV000149133 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.610G>A at the cDNA level, p.Gly204Arg (G204R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has been observed in individuals with breast and/or ovarian cancer, in an individual with rhabdomyosarcoma, and in an individual with chronic lymphocytic leukemia (Zhang 2015, Nadeu 2016, Decker 2017, Singh 2018). ATM Gly204Arg was observed at an allele frequency of 0.01% (27/276,836) 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Gly204Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122868 SCV000166126 likely benign Ataxia-telangiectasia syndrome 2019-12-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115224 SCV000184444 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000115224 SCV000537552 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235097 SCV000780399 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000235097 SCV000805595 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000235097 SCV000861881 uncertain significance not provided 2018-06-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764935 SCV000896107 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122868 SCV001262432 uncertain significance Ataxia-telangiectasia syndrome 2017-04-28 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV001193006 SCV001361525 uncertain significance not specified 2019-02-28 criteria provided, single submitter clinical testing Variant summary: ATM c.610G>A (p.Gly204Arg), results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.8e-05 in 276836 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (9.8e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.610G>A, has been reported in the literature in individuals affected with breast and/or ovarian cancer, chronic lymphocytic leukemia and rhabdosarcoma (Tung 2015, Decker 2017, Singh 2018, Nadeu 2016, Tiao 2017, Zhang 2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA1 c.5172dupA, p.Glu1725Argfs*7), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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