ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.496+4T>C (rs587781375)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129193 SCV000183932 likely benign Hereditary cancer-predisposing syndrome 2019-02-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000211949 SCV000209584 benign not specified 2014-06-23 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 RCV000474202 SCV000546724 likely benign Ataxia-telangiectasia syndrome 2020-11-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585055 SCV000692729 uncertain significance not provided 2017-07-01 criteria provided, single submitter clinical testing
Counsyl RCV000474202 SCV000799740 uncertain significance Ataxia-telangiectasia syndrome 2018-05-03 criteria provided, single submitter clinical testing
Mendelics RCV000474202 SCV000838471 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129193 SCV000902853 likely benign Hereditary cancer-predisposing syndrome 2016-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211949 SCV000916580 uncertain significance not specified 2020-09-28 criteria provided, single submitter clinical testing Variant summary: ATM c.496+4T>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. 4/4 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 8.8e-05 in 251312 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in ATM causing Breast Cancer (8.8e-05 vs 0.001), allowing no conclusion about variant significance. c.496+4T>C has been reported in the literature in individuals affected with Breast Cancer (Jalkh_2017, Mitchell_2018). These reports do not provide unequivocal conclusions about association of the variant with disease. In addition, in one of these cases a co-occurrence with a possible pathogenic variant in the STK11 gene has been reported (c.375-1C>T, Jalkh_2017) providing supporting evidence for a benign role. The variant was also reported in 2/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other 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 (likely benign 2x, VUS 5x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000474202 SCV001520233 uncertain significance Ataxia-telangiectasia syndrome 2020-06-25 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000129193 SCV001911465 likely benign Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The intronic c.496+4T>C 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 (BP4). Splicing analysis in carrier RNA with proper design and controls showed only the wild-type transcript although do not demonstrate biallelic expression by an exonic SNV (BS3_Supporting; O.Díez, unpublished data). This variant has an allele frequency of 0.000082 (0.008%, 22/268,180 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00019 (0.02%, 22/118,056 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 + BS3_Supporting (PMID: 33280026).
True Health Diagnostics RCV000129193 SCV000787868 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-21 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357828 SCV001553415 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM c.496+4T>C variant was identified in 4 of 2610 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and Lynch Syndrome (Jalkh 2017,Yurgelun 2015, ). The variant was identified in dbSNP (rs587781375) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Counsyl, Integrated Genetics and 4 other submitters, benign by GeneDx and likely benign by Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 23 of 282,719 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 23 of 129,072 chromosomes (freq: 0.0002), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The variant was reported in an individual with a co-occurring pathogenic STK11 variant (c.375-1C>T) (Jalkh 2017). The c.496+4T>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 4 out of 4 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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