ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7390T>C (p.Cys2464Arg) (rs55801750)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589438 SCV000149158 likely benign not provided 2021-09-22 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30093976, 30303537, 30197789, 17623063, 20305132, 22250480, 21933854, 23555315, 25479140, 28135145, 28779002, 25587027, 15279808, 22420423, 12810666, 27978560, 27878467, 26787654, 17344846, 11805335, 11606401, 11839094, 16652348, 12673804, 23091097, 22529920, 19781682)
Invitae RCV000119204 SCV000153946 benign Ataxia-telangiectasia syndrome 2020-12-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115249 SCV000186389 benign Hereditary cancer-predisposing syndrome 2015-11-12 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);No disease association in appropriately sized case-control study(ies)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000202803 SCV000257606 uncertain significance not specified 2015-07-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202803 SCV000694351 benign not specified 2019-02-22 criteria provided, single submitter clinical testing Variant summary: ATM c.7390T>C (p.Cys2464Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00042 vs 0.001). However, this variant has been reported in 16/9884 (0.0016) women older than age 70 and cancer free. This frequency is higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0016 vs 0.001), suggesting this variant does not associate with cancer. c.7390T>C has been reported in the literature in individuals affected with Breast Cancer. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (CHEK2 c.1100delC, p.Thr367fsX15; TP53 c.782+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (1x Benign, 2 x Likely benign, 4x VUS). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000119204 SCV000743734 uncertain significance Ataxia-telangiectasia syndrome 2016-10-06 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000119204 SCV000745131 uncertain significance Ataxia-telangiectasia syndrome 2016-02-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589438 SCV000780404 uncertain significance not provided 2018-01-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115249 SCV000910578 benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Mendelics RCV000119204 SCV001138562 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119204 SCV001261060 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286470 SCV001473046 likely benign none provided 2019-10-31 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000115249 SCV001911484 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.7390T>C (p.Cys2464Arg) variant has an allele frequency of 0.00043 (0.04%, 114/268,152 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00092 (0.09%, 109/118,016 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356727 SCV001551971 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Cys2464Arg variant was identified in 25 of 16960 proband chromosomes (frequency: 0.002) from individuals or families with B chronic lymphocytic leukemia, breast cancer or pancreatic cancer and was present in 18 of 5488 control chromosomes (frequency: 0.003) from healthy individuals (Athanasakis 2014, Bernstein 2010, Decker 2017, Dork 2001, Grant 2015, Skowronska 2012, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs55801750) as "With other allele", ClinVar (classified as Benign by Ambry Genetics; as likely benign by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by four submitters), and in LOVD 3.0 (2x as unclassified variant). The variant was identified in control databases in 118 of 277014 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6460 chromosomes (freq: 0.0002), European in 114 of 126536 chromosomes (freq: 0.0009), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Cys2464 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.

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