Submissions for variant NM_000546.6(TP53):c.97-9C>T

gnomAD frequency: 0.00011  dbSNP: rs202217267

Total submissions: 11

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	2022-11-03	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 Diagnostics, LLC DBA Color Health	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.
Genetic Services Laboratory, University of Chicago	RCV000161046	SCV002070160	likely benign	not specified	2020-02-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000580612	SCV002532732	benign	Hereditary cancer-predisposing syndrome	2021-03-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000161046	SCV002551136	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410371	SCV004017841	likely benign	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
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.