ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.412G>C (p.Ala138Pro) (rs28934875)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461233 SCV000545311 likely pathogenic Li-Fraumeni syndrome 2016-11-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 138 of the TP53 protein (p.Ala138Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (rs28934875, ExAC no frequency). This variant has been reported to segregate with Li-Fraumeni syndrome-related cancers (adrenocortical carcinoma, rhabdomyosarcoma, chondrosarcoma, breast cancer) in a single family (PMID: 9569035, 17567834). ClinVar contains an entry for this variant (Variation ID: 12376). Experimental studies have shown that this missense change nearly abolishes TP53 transactivation activity, and that it may act in a dominant-negative manner to decrease wild-type TP53 activity as well (PMID: 21343334, 17606709, 15548685, 19958544, 12826609). In summary, this variant is a rare missense change that disrupts protein activity and has been observed in affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000013175 SCV000033422 pathogenic Li-Fraumeni syndrome 1 1998-04-01 no assertion criteria provided literature only

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