ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.704A>G (p.Asn235Ser) (rs144340710)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115733 SCV000185528 likely benign Hereditary cancer-predisposing syndrome 2018-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Intact protein function observed in appropriate functional assay(s),Does not segregate with disease in family study (genes with incomplete penetrance)
CSER_CC_NCGL; University of Washington Medical Center RCV000148915 SCV000190661 uncertain significance Rhabdomyosarcoma 2014-06-01 no assertion criteria provided research
Color RCV000115733 SCV000902685 benign Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing
Counsyl RCV000663295 SCV000786543 likely benign Li-Fraumeni syndrome 1 2018-05-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590586 SCV000232075 uncertain significance not provided 2014-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000122177 SCV000149642 likely benign not specified 2017-10-26 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago RCV000122177 SCV000597513 uncertain significance not specified 2016-09-13 criteria provided, single submitter clinical testing
ITMI RCV000122177 SCV000086392 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000590586 SCV000697446 likely benign not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The TP53 c.704A>G (p.Asn235Ser) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome. Of note, some fish have a Serine instead of Asparagine at this amino acid position. Functional studies have shown this variant to have normal DNA binding properties and a residual transcriptional activity of >70%, while the majority of known pathogenic TP53 variants have a transcriptional activity of <20%. Additionally, immunohistochemical staining of tumors with Asn235Ser showed no expression of p53, while positive staining is commonly seen for pathogenic TP53 missense mutations. This variant was found in 30/121638 control chromosomes at a frequency of 0.0002466, which is approximately 6 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398), suggesting this variant is likely a benign polymorphism. The variant has been identified as a somatic and germline variant in cancer patients reported in the literature. However, the variant was shown to not co-segregate with disease in at least one LFS family, who also carried a pathogenic splice site TP53 variant (van Hest_Fam Canc_2007), suggesting that the variant of interest was not the cause of LFS in this family. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Although the large majority of evidence is in favor of the conclusion that this variant is a benign polymorphism with respect to LFS, it cannot be ruled out that this variant may be a low penetrance allele associated with cancer risk. Taken together, this variant is classified as Likely Benign until additional co-segregation studies definitely prove that this variant is a benign polymorphism.
Invitae RCV000168433 SCV000219130 likely benign Li-Fraumeni syndrome 2017-12-19 criteria provided, single submitter clinical testing

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