ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.566C>T (p.Ala189Val) (rs121912665)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132058 SCV000187120 likely benign Hereditary cancer-predisposing syndrome 2019-08-30 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
Counsyl RCV000144671 SCV000488324 uncertain significance Li-Fraumeni syndrome 1 2016-02-25 criteria provided, single submitter clinical testing
Invitae RCV000536677 SCV000629841 uncertain significance Li-Fraumeni syndrome 2020-03-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 189 of the TP53 protein (p.Ala189Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs121912665, ExAC 0.05%). This variant has been reported in the literature in individuals affected with multiple primary colon tumors (PMID: 12524418), breast cancer (PMID: 23667851, 27374712, 30287823) and fallopian tube carcinoma (PMID: 29770616), as well as in unaffected controls (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 12382). Experimental studies have shown that this missense change exhibits partial or full transactivation activity similar to the wild-type in yeast-based assays (PMID: 12826609, 24594805, 15037740, 21343334). 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.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030736 SCV001193752 benign Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Color Health, Inc RCV000132058 SCV001354218 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192620 SCV001360870 likely benign not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: TP53 c.566C>T (p.Ala189Val) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 308910 control chromosomes (gnomAD, other databases and publication). The observed variant frequency is approximately 5.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), predominantly at a frequency of 0.0011 within the Japanese subpopulation, strongly suggesting that the variant is benign. c.566C>T has been reported in the literature in individuals affected with different type of cancer (Miyaki_2003, Cho_2013, Park_2016, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Functional studies report this variant showed no damaging effect of this variant (Monti_2011, Kato_2003). Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000013182 SCV000033429 pathogenic Familial colorectal cancer 2003-02-01 no assertion criteria provided literature only
Pathway Genomics RCV000144671 SCV000190003 uncertain significance Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing

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