ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.993G>A (p.Gln331=) (rs11575996)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492456 SCV000581098 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000521745 SCV000617733 likely pathogenic not provided 2018-06-20 criteria provided, single submitter clinical testing This variant is denoted TP53 c.993G>A at the DNA level. Although this variant is silent at the coding level, preserving a Glutamine at codon 331, it is predicted to destroy the natural splice donor site for intron 9 and cause abnormal splicing. This variant was identified in a patient with adrenocortical carcinoma (ACC) at age 6, in this patient's mother who was diagnosed with breast cancer at age 37, as well as in an individual with early-onset breast and colon cancer (Magnusson 2012, Stoltze 2018). An in vitro study revealed expression of only the wild-type allele, suggesting that the variant resulted in an unstable transcript that was degraded (Magnusson 2012). TP53 c.993G>A was not observed in large population cohorts (Lek 2016). Based on currently available evidence and internal data, we consider TP53 c.993G>A to be a likely pathogenic variant.
Invitae RCV000685844 SCV000813343 likely pathogenic Li-Fraumeni syndrome 2018-06-05 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 of the TP53 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in families with suspected Li-Fraumeni syndrome (PMID: 22653678, 29324801). ClinVar contains an entry for this variant (Variation ID: 428868). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this silent change results in low levels of mRNA, stemming from unstable transcripts (PMID: 22653678). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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