ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.320A>G (p.Tyr107Cys)

dbSNP: rs587782447
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132052 SCV000187114 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing The p.Y107C variant (also known as c.320A>G), located in coding exon 3 of the TP53 gene, results from an A to G substitution at nucleotide position 320. The tyrosine at codon 107 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported as a somatic mutation one time in a tumor but not as a germline mutation by the IARC TP53 database (Bouaoun L et al. IARC TP53 database [version R18, April 2016]. Hum. Mutat. 2016 Sep;37:865-76). This variant is in the DNA binding domain of the TP53 protein and is reported to have partial transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Additional studies in human cell lines show that this alteration retains the ability to suppress cell growth (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8). This amino acid position is well conserved through mammals but not in lower vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics RCV000709408 SCV000839123 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000709408 SCV001226818 uncertain significance Li-Fraumeni syndrome 2021-08-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 107 of the TP53 protein (p.Tyr107Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC 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: 142691). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644). 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 RCV000132052 SCV001736272 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-04 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 107 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). The mutant protein has shown a dominant negative effect and loss-of-function phenotype in one human cell growth assay (PMID: 30224644), while showing normal function in another assay (PMID: 29979965). 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.
Genome-Nilou Lab RCV000132052 SCV002582119 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002288652 SCV002582681 uncertain significance Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing

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