ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235097 SCV000149133 uncertain significance not provided 2020-12-16 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 24356096, 27720647, 26580448, 26837699, 28873162, 29470806, 29522266, 25186627)
Invitae RCV000122868 SCV000166126 likely benign Ataxia-telangiectasia syndrome 2020-11-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115224 SCV000184444 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-30 criteria provided, single submitter clinical testing The p.G204R variant (also known as c.610G>A), located in coding exon 5 of the ATM gene, results from a G to A substitution at nucleotide position 610. The glycine at codon 204 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported as a germline alteration in a cohort of individuals with chronic lymphocytic leukemia (Nadeu F et al. Blood. 2016 04;127:2122-30). This alteration was detected in 1/5589 German BRCA1 and BRCA2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration has also been reported in 1/1010 unrelated patients with breast and/ovarian cancer from India (Singh J et al. Breast Cancer Res. Treat., 2018 Jul;170:189-196). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000115224 SCV000537552 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-30 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 204 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been observed in several individuals affected with breast or ovarian cancer (PMID: 20305132, 25186627, 28779002, 29470806), and in two individuals affected with chronic lymphocytic leukemia (PMID: 26837699, 28652578) and in 6 unaffected controls (PMID: 28652578). This variant has also been identified in 29/282440 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193006 SCV001361525 likely benign not specified 2021-02-12 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 0.00011 in 251150 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00011 vs 0.001), allowing no conclusion about variant significance. c.610G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer, chronic lymphocytic leukemia and rhabdosarcoma in settings of multigene panel testing and in unaffected control cohorts (example, Tung 2015, Decker 2017, Singh 2018, Nadeu 2016, Tiao 2017, Zhang 2015, Bonache_2018, Girard_2019). These reports do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia or Breast Cancer. At-least one co-occurrence with another pathogenic variant has been reportedin an individual undergoing multigene panel testing for breast cancer (BRCA1 c.5172dupA, p.Glu1725Argfs*7, Tung_2015), providing supporting evidence for a benign role. A recent study that included this variant reports that carriers of loss of function variants in the ATM gene have a significantly higher risk of developing breast cancer than carriers of an ATM missense variant (OR for LOF =17.4; OR for missense = 1.6) (Girard_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. At-least one other submitter has recently re-classified this variant as likely benign. Based on the absence of evidence supporting an actionable outcome as evidence outlined above, the variant was re-classified as likely benign.
GenomeConnect - Invitae Patient Insights Network RCV001535620 SCV001749645 not provided Ataxia-telangiectasia syndrome; Malignant tumor of breast no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 05-06-2016 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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