Submissions for variant NM_000546.6(TP53):c.605G>A (p.Arg202His)

dbSNP: rs587778719

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459232	SCV000545288	uncertain significance	Li-Fraumeni syndrome	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 202 of the TP53 protein (p.Arg202His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 135358). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect 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.
Ambry Genetics	RCV000567735	SCV000664400	likely benign	Hereditary cancer-predisposing syndrome	2019-02-15	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.
Color Diagnostics, LLC DBA Color Health	RCV000567735	SCV000691603	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 202 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have indicated that this variant does not impair protein function (PMID 12826609, 24665023, 30224644, 29979965). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 30287823), but also in healthy individuals (PMID: 24728327, 30287823, 32980694, 33471991). 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030735	SCV001193751	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV000459232	SCV004823779	uncertain significance	Li-Fraumeni syndrome	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 202 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have indicated that this variant does not impair protein function (PMID 12826609, 24665023, 30224644, 29979965). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 30287823), but also in healthy individuals (PMID: 24728327, 30287823, 32980694, 33471991). 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.
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.