ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1060C>A (p.Gln354Lys)

gnomAD frequency: 0.00002  dbSNP: rs755394212
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000663226 SCV001949924 likely benign Li-Fraumeni syndrome 1 2021-08-02 reviewed by expert panel curation Transactivation assays show supertransactivation function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, TP53 c.1060C>A (p.Gln354Lys) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting.
Ambry Genetics RCV000222255 SCV000275352 likely benign Hereditary cancer-predisposing syndrome 2021-02-02 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.
Invitae RCV000469791 SCV000545335 uncertain significance Li-Fraumeni syndrome 2023-10-30 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 354 of the TP53 protein (p.Gln354Lys). This variant is present in population databases (rs755394212, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24549055, 34326862). ClinVar contains an entry for this variant (Variation ID: 231485). 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). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626710 SCV000747413 uncertain significance Colorectal polyposis; Colonic neoplasm 2017-01-01 criteria provided, single submitter clinical testing
Counsyl RCV000663226 SCV000786422 uncertain significance Li-Fraumeni syndrome 1 2018-05-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000222255 SCV001359324 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-16 criteria provided, single submitter clinical testing This missense variant replaces glutamine with lysine at codon 354 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant was functional in yeast transactivation assays (PMID: 12826609) and did not demonstrate dominant-negative or loss-of-function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 24549055, 33471991) but also in controls and individuals unselected for cancer (PMID: 28861920, 33471991). This variant has been identified in 5/250864 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001269248 SCV001448570 uncertain significance not specified 2020-11-27 criteria provided, single submitter clinical testing Variant summary: TP53 c.1060C>A (p.Gln354Lys) results in a conservative amino acid change located in the p53, tetramerization domain (IPR010991) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250864 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1060C>A has been reported in the literature in at-least one individual affected with breast cancer (example, Castero_2014). This report(s) does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Kato_2003). These results showed no damaging effect of this variant based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4 RCV000222255 SCV002530422 likely benign Hereditary cancer-predisposing syndrome 2022-01-24 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000663226 SCV004017866 uncertain significance Li-Fraumeni syndrome 1 2023-04-11 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.
All of Us Research Program, National Institutes of Health RCV000469791 SCV004823723 uncertain significance Li-Fraumeni syndrome 2023-09-18 criteria provided, single submitter clinical testing This missense variant replaces glutamine with lysine at codon 354 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant was functional in yeast transactivation assays (PMID: 12826609) and did not demonstrate dominant-negative or loss-of-function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 24549055, 33471991) but also in controls and individuals unselected for cancer (PMID: 28861920, 33471991). This variant has been identified in 5/250864 chromosomes 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.

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