ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.532C>G (p.His178Asp) (rs1064795203)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000633339 SCV001142544 likely pathogenic Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). Additionally, there was a de novo observation in an individual with rhabdomyosarcoma and a sarcoma of the tibia under the age of 8 years without mention of parental confirmation (PM6; PMID: 19701813). In summary, TP53 c.532C>G; p.His178Asp meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PS3, PM6.
Ambry Genetics RCV000575494 SCV000667198 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence,Other data supporting pathogenic classification,Other strong data supporting pathogenic classification
Invitae RCV000633339 SCV000754561 likely pathogenic Li-Fraumeni syndrome 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 178 of the TP53 protein (p.His178Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with embryonal rhabdomyosarcoma and osteosarcoma (PMID: 21345075). It was also observed in individuals affected with breast cancer (PMID: 26094658, 28961279). Experimental studies in yeast and human cells have shown that this missense change impairs the normal function of the TP53 protein (PMID: 12826609, 22829111, 24814347). 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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