ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.215C>A (p.Pro72His)

dbSNP: rs1042522
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV001527080 SCV001737917 likely benign Li-Fraumeni syndrome 1 2021-04-19 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). ). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644) Finally, this variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting, Invitae internal data). In summary, TP53 c.215C>A; p.Pro72His meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_supporting, BP4, BS3, BS2_supporting. PM2_Supporting should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification.
Ambry Genetics RCV000164487 SCV000215135 likely benign Hereditary cancer-predisposing syndrome 2021-03-26 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000227427 SCV000285179 uncertain significance Li-Fraumeni syndrome 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 72 of the TP53 protein (p.Pro72His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 185120). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV000164487 SCV000903442 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-15 criteria provided, single submitter clinical testing This missense variant replaces proline with histidine at codon 72 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4 RCV000164487 SCV002530433 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-10 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV000227427 SCV004823833 uncertain significance Li-Fraumeni syndrome 2023-03-28 criteria provided, single submitter clinical testing This missense variant replaces proline with histidine at codon 72 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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