ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5497-15G>C

gnomAD frequency: 0.00363  dbSNP: rs3092828
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000123750 SCV000167093 benign not specified 2013-12-20 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.
PreventionGenetics, part of Exact Sciences RCV000123750 SCV000301672 benign not specified criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000447093 SCV000537400 benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001103816 SCV001260628 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123750 SCV001362537 benign not specified 2019-04-05 criteria provided, single submitter clinical testing Variant summary: ATM c.5497-15G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0044 in 276392 control chromosomes, predominantly at a frequency of 0.012 within the Finnish subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. The variant, c.5497-15G>C, has been reported in the literature in individuals affected with Cancer (Angele_2004, Birrell_2005, Heikkinen_2005). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported (ATM c.5664_5665insC; ATM c.7307+1G>A; both in trans) in one patient associated with ataxia telangiectasia (Birrell_2005). This further supports a benign outcome due to the presence of this variant in cis with a pathogenic variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001689673 SCV001471100 benign not provided 2023-11-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001103816 SCV001718572 benign Ataxia-telangiectasia syndrome 2024-02-01 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225399 SCV002504732 benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000447093 SCV002650079 likely benign Hereditary cancer-predisposing syndrome 2015-08-13 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000123750 SCV002760586 likely benign not specified 2023-08-15 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003149850 SCV003837791 benign Breast and/or ovarian cancer 2021-06-02 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001689673 SCV003916781 likely benign not provided 2023-06-01 criteria provided, single submitter clinical testing ATM: BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV003315838 SCV004016564 benign Familial cancer of breast 2023-07-07 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003315838 SCV005083953 benign Familial cancer of breast 2024-05-23 criteria provided, single submitter clinical testing This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358583 SCV001554364 benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM c.5497-15G>C variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs3092828) as “With Benign allele”, and ClinVar (3x benign from GeneDx, Prevention Genetics, Color Genomics). The variant was not identified in GeneInsight-COGR, COSMIC, MutDB, LOVD 3.0, or the ATM-LOVD databases. The variant was identified in control databases in 1213 (5 homozygous) of 276392 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Finnish) in 304 of 25704 chromosomes (freq: 0.01). The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, this variant is classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000123750 SCV001807467 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV001689673 SCV001906454 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000123750 SCV001920085 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000123750 SCV001930036 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001689673 SCV001957761 likely benign not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001689673 SCV002036378 likely benign not provided no assertion criteria provided clinical testing

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