Submissions for variant NM_000546.6(TP53):c.672+1G>T

dbSNP: rs863224499

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000776760	SCV000912404	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 6 of the TP53 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with rhabdomyosarcoma meeting Chompret criteria (PMID: 32658383), breast cancer (PMID: 20805372, 25564201), and hairy cell leukemia variant (PMID 34607348). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269151	SCV001448415	pathogenic	Li-Fraumeni syndrome	2020-11-05	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.672+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251208 control chromosomes (gnomAD). c.672+1G>T has been reported in the literature in multiple individuals affected with primary tumors belonging to the Li-Fraumeni Syndrome (LFS) spectrum (e.g. Achatz_2006, Fitarelli-Kiehl_2015, Eccles_2016, Wilson_2010, Renaux-Petel_2017, Pondrom_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001269151	SCV002243941	pathogenic	Li-Fraumeni syndrome	2023-05-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 630765). This variant is also known as IVS6 +1G>T. Disruption of this splice site has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 16494995, 23409989, 29070607; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 6 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432).
Genome-Nilou Lab	RCV000776760	SCV002582371	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290025	SCV002583031	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785529	SCV000924101	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786829	SCV000925723	not provided	not provided		no assertion provided	in vitro
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001644809	SCV001860282	pathogenic	Breast carcinoma	2021-09-14	no assertion criteria provided	clinical testing