Submissions for variant NM_000546.6(TP53):c.672G>A (p.Glu224=)

dbSNP: rs267605076

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567974	SCV000665290	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The c.672G>A pathogenic mutation (also known as p.E224E), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 672. This mutation has been identified in several patients meeting Chompret criteria (Gallardo-Alvarado LN et al. BMC Cancer, 2019 Feb;19:118; Ambry internal data). This mutation was also reported as occurring de novo in a 17 year old individual diagnosed with two sarcomas (Austin F et al. Pediatr Blood Cancer, 2017 Nov;64:). This nucleotide substitution does not change the at codon 224. However, this change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. An in vivo splicing assay has shown that this alteration results in aberrant splicing which activates a cryptic splice site, resulting in a frameshifted mRNA (Supek F et al. Cell, 2014 Mar;156:1324-1335). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800846	SCV000940585	pathogenic	Li-Fraumeni syndrome	2024-10-25	criteria provided, single submitter	clinical testing	This sequence change affects codon 224 of the TP53 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TP53 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Li-Fraumeni syndrome associated tumors (PMID: 28475293). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 80709). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 24630730, 28475293; internal data). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000567974	SCV002582372	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288559	SCV002583033	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288559	SCV004930373	likely pathogenic	Li-Fraumeni syndrome 1	2024-01-10	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28475293]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28475293, 30709381].
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786830	SCV000925724	not provided	not provided		no assertion provided	in vitro