Submissions for variant NM_000546.6(TP53):c.993G>A (p.Gln331=)

dbSNP: rs11575996

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492456	SCV000581098	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-02-24	criteria provided, single submitter	clinical testing	The c.993G>A variant (also known as p.Q331Q) is located in coding exon 8 of the TP53 gene. This variant results from a G to A substitution at nucleotide position 993. This nucleotide substitution does not change the glutamine at amino acid 331. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in a child with adrenocortical carcinoma at age six whose mother was diagnosed with breast cancer at age 37. Sequence analysis of cDNA showed expression of the wild type allele only, indicating that the alteration may lead to unstable mRNA transcript that is subject to nonsense mediated decay (Magnusson S et al. Pediatr Blood Cancer. 2012 Nov;59(5):846-53). The c.933G>A variant has also been reported in a female diagnosed with breast cancer at age 35 (Stoltze U et al. PLoS One. 2018 Jan;13:e0190050). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000521745	SCV000617733	likely pathogenic	not provided	2021-02-22	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; Published functional studies revealed expression of only the wild-type allele, suggesting that the variant resulted in an unstable transcript that was degraded (Magnusson 2012); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 14678961, 30720243, 24665023, 15347601, 17062677, 18798306, 22653678, 29324801, 31081129)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685844	SCV000813343	pathogenic	Li-Fraumeni syndrome	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change affects codon 331 of the TP53 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TP53 protein. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of TP53 related conditions (PMID: 22653678, 29324801, 33674644). ClinVar contains an entry for this variant (Variation ID: 428868). Studies have shown that this variant alters TP53 gene expression (PMID: 22653678). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000492456	SCV002582338	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289663	SCV002583000	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
BRCAlab, Lund University	RCV000492456	SCV002589038	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	no assertion criteria provided	clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000521745	SCV002822971	not provided	not provided		no assertion provided	research