ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4388T>G (p.Phe1463Cys) (rs138327406)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000588436 SCV000602567 likely benign not provided 2017-08-24 criteria provided, single submitter clinical testing The ATM c.4388T>G;p.Phe1463Cys variant (rs138327406) has been previously reported in cohorts of early onset breast cancer (Maillet 2002), Hodgkin’s lymphoma (Liberzon 2004) and both (Offit 2002). However, as listed in the ExAC browser, this variant has a high frequency in the general population (0.14%; identified in 164 out of 118,972 chromosomes, including 3 homozygotes), and in one study (Offit 2002), this variant was found at equal frequencies in cases and controls (1.56%). This variant is also listed in the ClinVar database as likely benign or benign (Variation ID: 127388), and has been classified as likely benign by a consortium of clinical labs examining variants associated with breast cancer (Maxwell 2016). Thus, the p.Phe1463Cys variant is likely to be benign. References: ClinVar link to ATM variant: https://www.ncbi.nlm.nih.gov/clinvar/variation/127388/ Liberzon et al. Molecular variants of the ATM gene in Hodgkin's disease in children. Br J Cancer. 2004; 90(2): 522-525. Maxwell et al. Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet. 2016; 98(5): 801-817. Maillet et al. Constitutional alterations of the ATM gene in early onset sporadic breast cancer. J Med Genet. 2002; 39(10): 751-753. Offit et al. Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers. Clin Cancer Res. 2002; 8(12): 3813-3819.
Ambry Genetics RCV000115193 SCV000183891 benign Hereditary cancer-predisposing syndrome 2014-06-19 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000588436 SCV000840940 benign not provided 2017-11-22 criteria provided, single submitter clinical testing
Color RCV000115193 SCV000682201 benign Hereditary cancer-predisposing syndrome 2014-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000122848 SCV000797992 likely benign Ataxia-telangiectasia syndrome 2018-02-22 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000588436 SCV000228685 uncertain significance not provided 2015-02-05 criteria provided, single submitter clinical testing
GeneDx RCV000120139 SCV000149102 benign not specified 2017-05-26 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago RCV000120139 SCV000593483 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing
ITMI RCV000120139 SCV000084279 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000588436 SCV000694279 likely benign not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The ATM c.4388T>G (p.Phe1463Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have not been validated by any in vitro/vivo functional studies. This variant was found in 172/120622 control chromosomes (3 homozygotes) at a frequency of 0.0014259, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic ATM variant for breast cancer (0.0005001), suggesting this variant does not cause breast cancer. The variant was found in 149/65460 European non-Finnish chromosomes (0.002276) with 3 homozygotes; while this frequency does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant for Ataxia-telangiectasia (AT; 0.0039528), AT is a childhood disorder, and thus it would be unlikely for there to be 3 homozygous unaffected individuals in the ExAC database. Furthermore, it has been shown that while heterozygotes are not at increased risk of developing A-T neurologic manifestations, they have a fourfold increased risk of developing breast cancer through mechanisms that are not understood. Thus, if this were a pathogenic AT-causing variant, it would increase the risk of breast cancer. However, population control data strongly indicate that this variant does not cause breast cancer.This variant has been reported in patients with a variety types of cancers such as BrC, HD, HBOC, B-CLL, OvC, Pancreatic Cancer, and hemangioblastomas, however, there was no strong evidence to support the causative correlation of this variant with the diseases. Additionally, the variant was found to co-occur with likely pathogenic variants (BRIP1 c.440dupA and ATM c.1027_1030delGAAA) in internal specimens tested for cancer risk.Two clinical laboratories (via ClinVar) classified this variant as benign, one classified this variant as likely benign, and two labs classified it as VUS, without evidence to independently evaluate. Considering all, the variant was classified as Likely Benign until additional information becomes available.
Invitae RCV000122848 SCV000166106 benign Ataxia-telangiectasia syndrome 2018-01-15 criteria provided, single submitter clinical testing
Mendelics RCV000122848 SCV000838538 likely benign Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000120139 SCV000805563 benign not specified 2017-05-30 criteria provided, single submitter clinical testing
Vantari Genetics RCV000115193 SCV000266992 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-26 criteria provided, single submitter clinical testing

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