ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.97-9C>T (rs202217267)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161046 SCV000211776 benign not specified 2014-06-10 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 RCV001079867 SCV000253318 likely benign Li-Fraumeni syndrome 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000410371 SCV000488528 uncertain significance Li-Fraumeni syndrome 1 2016-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000195920 SCV000602284 likely benign not provided 2020-04-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000580612 SCV000686786 likely benign Hereditary cancer-predisposing syndrome 2016-04-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000161046 SCV001370686 benign not specified 2020-05-26 criteria provided, single submitter clinical testing Variant summary: TP53 c.97-9C>T 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 0.00014 in 250376 control chromosomes. The observed variant frequency is approximately 3.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.97-9C>T in individuals affected with Li-Fraumeni Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000410371 SCV001552654 likely benign Li-Fraumeni syndrome 1 no assertion criteria provided clinical testing The TP53 c.97-9C>T variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs202217267) as "With other allele" and ClinVar (classified as benign by GeneDx; as likely benign by Invitae, Color and Quest Diagnostics Nichols Institute San Juan Capistrano; and as uncertain significance by Counsyl). The variant was identified in control databases in 35 of 276116 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 32 of 126596 chromosomes (freq: 0.0003, increasing the likelihood this could be a low frequency benign variant), Latino in 2 of 34398 chromosomes (freq: 0.00006), and Finnish in 1 of 24966 chromosomes (freq: 0.00004), while it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or South Asian populations. The c.97-9C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. Positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; however, 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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