Submissions for variant NM_000546.6(TP53):c.920-5C>T

gnomAD frequency: 0.00003  dbSNP: rs34361146

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164926	SCV000215614	likely benign	Hereditary cancer-predisposing syndrome	2019-02-28	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087552	SCV000557372	likely benign	Li-Fraumeni syndrome	2024-12-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001283870	SCV000697456	benign	not specified	2022-01-16	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.920-5C>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 5.2e-05 in 251470 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 18 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 a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.920-5C>T in individuals affected with Li-Fraumeni Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000164926	SCV000902814	likely benign	Hereditary cancer-predisposing syndrome	2016-08-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587880	SCV001151191	uncertain significance	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283870	SCV001469328	benign	not specified	2019-12-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164926	SCV002532725	likely benign	Hereditary cancer-predisposing syndrome	2021-07-17	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV001087552	SCV005425712	likely benign	Li-Fraumeni syndrome	2024-08-13	criteria provided, single submitter	clinical testing