ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.605G>A (p.Arg202His) (rs587778719)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459232 SCV000545288 uncertain significance Li-Fraumeni syndrome 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 202 of the TP53 protein (p.Arg202His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer and healthy control individuals (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 135358). Experimental studies have shown that this variant does not substantially affect TP53 protein function (PMID: 12826609, 30224644, 29979965). 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.
Ambry Genetics RCV000567735 SCV000664400 likely benign Hereditary cancer-predisposing syndrome 2019-02-15 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Other strong data supporting benign classification
Color Health, Inc RCV000567735 SCV000691603 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-07 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030735 SCV001193751 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
ITMI RCV000122175 SCV000086390 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358628 SCV001554419 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The TP53 p.Arg202His variant was identified in dbSNP (ID: rs587778719) as “With Uncertain significance, other allele”, ClinVar (classified as likely benign by Ambry Genetics and as uncertain significance by Invitae and Color), and LOVD 3.0 (3x as a variant of uncertain significance). The variant was also identified in the literature in patients with acute leukemia and renal cell carcinoma, in a breast carcinoma tumour, and in one healthy individual in a normal population study (Azuma 2017, Bousquet 2015, Bodian 2014, Lukas 2000). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Arg202 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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