Submissions for variant NM_000546.6(TP53):c.97-3C>T

dbSNP: rs786203749

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001527082	SCV001737921	uncertain significance	Li-Fraumeni syndrome 1	2021-04-02	reviewed by expert panel	curation	This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, the clinical significance of TP53 c.97-3C>T is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BS2_Supporting.
Ambry Genetics	RCV000167188	SCV000218025	likely benign	Hereditary cancer-predisposing syndrome	2021-01-05	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	RCV000465475	SCV000545323	likely benign	Li-Fraumeni syndrome	2024-07-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000478081	SCV000567393	uncertain significance	not provided	2016-04-09	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.97-3C>T or IVS3-3C>T and consists of a C>T nucleotide substitution at the -3 position of intron 3 of the TP53 gene. This variant is not predicted to affect gene splicing. TP53 c.97-3C>T has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The cytosine (C) nucleotide that is altered is not conserved. Based on currently available information, it is unclear whether TP53 c.97-3C>T is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000167188	SCV000691672	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This variant causes a C>T nucleotide substitution at the -3 position of intron 3 of the TP53 gene. Splice site prediction tools do not indicate that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000167188	SCV002532731	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-05	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000465475	SCV004840071	uncertain significance	Li-Fraumeni syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This variant causes a C>T nucleotide substitution at the -3 position of intron 3 of the TP53 gene. Splice site prediction tools do not indicate that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800306	SCV005423051	uncertain significance	not specified	2024-10-07	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.97-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250846 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.97-3C>T in individuals affected with Li-Fraumeni Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 187457). Based on the evidence outlined above, the variant was classified as uncertain significance.