ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4388T>G (p.Phe1463Cys) (rs138327406)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000122848 SCV000166106 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115193 SCV000183891 benign Hereditary cancer-predisposing syndrome 2014-06-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000588436 SCV000228685 uncertain significance not provided 2015-02-05 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
Genetic Services Laboratory, University of Chicago RCV000120139 SCV000593483 likely benign not specified 2019-11-26 criteria provided, single submitter clinical testing
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: 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.
Color Health, Inc RCV000115193 SCV000682201 benign Hereditary cancer-predisposing syndrome 2014-12-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Counsyl RCV000122848 SCV000797992 likely benign Ataxia-telangiectasia syndrome 2018-02-22 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120139 SCV000805563 benign not specified 2017-05-30 criteria provided, single submitter clinical testing
Mendelics RCV000122848 SCV000838538 likely benign Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000588436 SCV000840940 benign not provided 2017-11-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588436 SCV001249804 likely benign not provided 2019-12-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122848 SCV001263903 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.
ITMI RCV000120139 SCV000084279 not provided not specified 2013-09-19 no assertion provided reference population
Natera, Inc. RCV000122848 SCV001462144 benign Ataxia-telangiectasia syndrome 2020-04-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356026 SCV001551080 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Phe1463Cys variant was identified in 12 of 4036 proband chromosomes (frequency: 0.00297) from individuals or families with breast cancer, ovarian cancer, Non-Hodgkin's lymphoma and Lynch syndrome (Liberzon 2004, Maillet 2002, Stafford 2017, Tung 2016, Yorczyk 2015, Yurgelun 2015). The variant was also identified in dbSBP (ID: rs138327406) as “With other allele”, ClinVar 6x with conflicting interpretations of pathogenicity (as uncertain significance by EGL Genetic and Vantari Genetics, as likely benign by GeneDx, and as benign by Invitae and Ambry Genetics), Clinvitae (4x), and Cosmic databases. The variant was not identified in MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 405 of 276966 chromosomes at a frequency of 0.001462 in the following populations: Ashkenazi Jewish in 274 (7 homozygous) of 10144 chromosomes (freq. 0.027), Other in 21 of 6456 chromosomes (freq. 0.0033), Latino in 35 of 34392 chromosomes (freq. 0.001), European (Non-Finnish) in 67 of 126564 chromosomes (freq. 0.0005) and African in 8 of 24014 (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Phe1463Cys variant was found to co-occur with p.Pro604Ser in 2 individuals with Non-Hodgkin’s lymphoma (Liberzon 2004). One study concluded that the p.Phe1463Cys variant is pathogenic in breast cancer because the amino acid substitution is known to be deleterious to ATM function in patients with B cell non-Hodgkin’s lymphomas, as well as based on conservation data (Maillet 2002). The p.Phe1463 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115193 SCV001950164 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-15 no assertion criteria provided clinical testing

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