ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.800G>A (p.Arg267Gln) (rs587780075)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115737 SCV000185134 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Well-characterized mutation at same position
Color RCV000115737 SCV000686776 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Counsyl RCV000662441 SCV000784905 uncertain significance Li-Fraumeni syndrome 1 2017-02-02 criteria provided, single submitter clinical testing
GeneDx RCV000213058 SCV000149646 uncertain significance not provided 2016-02-18 criteria provided, single submitter clinical testing This variant is denoted TP53 c.800G>A at the cDNA level, p.Arg267Gln (R267Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been reported in an affected child from a Li-Fraumeni syndrome family, co-occurring with two other TP53 variants (Quesnel 1999). This variant has also been identified in a woman who had breast cancer at age 49 and a family history of breast, ovarian, and colon cancers; however, the variant was also identified in a 74-year-old unaffected relative (Prosser 1992). TP53 Arg267Gln was reported in a child with adrenocortical carcinoma; however the child's mother also carried the variant and was unaffected, and there was no reported family history of cancer (Wasserman 2015). In addition, this variant has been identified in at least two colon cancer cases (Kandioler 2015). This variant has demonstrated mixed results in studies assessing transactivation activity, and although it has been shown to be deficient in colony reduction and have significantly reduced growth suppressive ability, it has yielded TP53 expression levels comparable to wild type (Quesnel 1999, Jordan 2010, Monti 2011, Wasserman 2015).Population frequency data is not available for TP53 Arg267Gln in the NHLBI Exome Sequencing Project or 1000 Genomes. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Arg267Gln occurs at a position that is not conserved and is located within the region of interaction with E4F1 (UniProt). One published splicing model predicts that TP53 Arg267Gln introduces a new splice acceptor site (Kouidou 2009), however internal splicing models are inconsistent regarding the effect of this variant on splicing. Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Arg267Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205433 SCV000260755 uncertain significance Li-Fraumeni syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 267 of the TP53 protein (p.Arg267Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587780075, ExAC 0.004%). This variant has been reported in a proband with breast cancer and her unaffected sister, three other members of the family with breast, cervical and lung cancers who were obligate carriers, as well as a 74-year-old unaffected family member. Segregation of this variant with disease in this family is thus uncertain (PMID: 1562462). This variant was found in an affected child from a Li-Fraumeni syndrome (LFS) family in whom it co-occurred with two other TP53 variants (PMID: 10435620), and in a child with adrenocortical carcinoma, but was inherited from an unaffected mother (PMID: 25584008). This variant has also been reported in unrelated individuals with suspected Li-Fraumeni syndrome (PMID: 17606709, 9667734, 27210295), but segregation studies were not performed. ClinVar contains an entry for this variant (Variation ID: 127823). Several experimental studies in yeast and human cell lines have shown that this missense change results in decreased transactivation activity compared to the wild-type TP53 protein (PMID: 10435620, 17606709, 20407015, 21343334, 12826609), and a partial growth suppression defect in human cells (PMID: 10435620, 25584008). It is thus considered a partial deficiency allele. An increase of transactivation function in a luciferase reporter assay has also been reported (PMID: 25584008). 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.

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