ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.832C>G (p.Pro278Ala) (rs17849781)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567850 SCV000665233 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-22 criteria provided, single submitter clinical testing The p.P278A variant (also known as c.832C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 832. The proline at codon 278 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in a patient meeting Chompret criteira (personal communication). This alteration has also been reported in a 1 of 109 women diagnosed with breast cancer who underwent genetic testing for suspected germline TP53 mutations (Melhem-Bertrandt A et al. Cancer. 2012 Feb;118:908-13). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in functional studies in yeast and human cell lines (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Jordan JJ et al. Mol. Cancer Res., 2010 May;8:701-16; Wang B et al. Cell Death Differ., 2014 Apr;21:521-32). Additional studies showed this variant to be deficient in DNA binding, apoptosis induction, and growth suppression (Wang B et al. Cell Death Differ. 2014 Apr;21:521-32; Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8). Other alterations at this same amino acid position (p.P278S, p.P278T) have previously been reported in the germline of individuals diagnosed with Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2001 Apr; 38(4):253-7; Güran S et al. Cancer Genet. Cytogenet. 2005 Jul; 160(2):164-8; Speiser P et al. Br. J. Cancer. 1996 Jul; 74(2):269-73). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in DNA binding (Petty TJ et al. EMBO J. 2011 Jun;30:2167-76; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000688854 SCV000816480 uncertain significance Li-Fraumeni syndrome 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 278 of the TP53 protein (p.Pro278Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast, ovarian, and/or other cancers (PMID: 21761402, 25428789, 27328919). ClinVar contains an entry for this variant (Variation ID: 376645). Experimental studies have shown that this missense change results in a protein that lacks normal transcriptional activity and does not promote apoptosis or repress proliferation properly (PMID: 24076587, 20407015, 12826609). 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.
Database of Curated Mutations (DoCM) RCV000437350 SCV000509086 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419216 SCV000509087 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426460 SCV000509088 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437992 SCV000509089 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420739 SCV000509090 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430547 SCV000509091 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441270 SCV000509092 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417926 SCV000509093 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427997 SCV000509094 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438674 SCV000509095 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422309 SCV000509096 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433017 SCV000509097 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439356 SCV000509098 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785477 SCV000924049 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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