Total submissions: 11
| 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 | This alteration is classified as likely benign based on a combination of the following: 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. |
| 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 | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 189 of the TP53 protein (p.Ala189Val). This variant is present in population databases (rs121912665, gnomAD 0.03%). This missense change has been observed in individual(s) with colon cancer, stomach cancer, lung cancer, breast cancer, and fallopian tube carcinoma (PMID: 12524418, 23667851, 27374712, 29770616, 30287823, 33309985). ClinVar contains an entry for this variant (Variation ID: 12382). Advanced modeling performed at Invitae incorporating data from internal and/or published 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). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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, |
RCV001030736 | SCV001193752 | likely benign | Hereditary breast ovarian cancer syndrome | 2022-03-30 | criteria provided, single submitter | research | |
| Color Diagnostics, |
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, |
RCV001192620 | SCV001360870 | likely benign | not specified | 2021-12-08 | 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 0.00027 in 316270 control chromosomes. The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. c.566C>T has been reported in the literature in individuals affected with different type of cancer (examples: Miyaki_2003, Cho_2013, Park_2016, Momozawa_2018, Shin_2020, Seo_2020, Fujita_2021, Alyami_2021 and Dorling _2021). 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). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign/benign (n=2) and as variant of uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign. |
| Sema4, |
RCV000132058 | SCV002530467 | likely benign | Hereditary cancer-predisposing syndrome | 2021-07-20 | criteria provided, single submitter | curation | |
| Myriad Genetics, |
RCV000144671 | SCV004017926 | uncertain significance | Li-Fraumeni syndrome 1 | 2023-04-12 | criteria provided, single submitter | clinical testing | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003476892 | SCV004221363 | likely benign | not provided | 2022-12-12 | criteria provided, single submitter | clinical testing | |
| 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 |