ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.396G>C (p.Lys132Asn)

dbSNP: rs866775781
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000709407 SCV001429628 likely pathogenic Li-Fraumeni syndrome 2022-03-18 reviewed by expert panel curation Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, TP53 c.396G>C (p.Lys132Asn) meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS3, PP3_Moderate, PM1, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000709407 SCV000949001 likely pathogenic Li-Fraumeni syndrome 2023-03-19 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Lys132 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 9157982, 18989156), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 376624). This missense change has been observed in individual(s) with breast cancer and/or clinical features of Li-Fraumeni syndrome (PMID: 32817165, 35264596; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 132 of the TP53 protein (p.Lys132Asn).
Mendelics RCV000424592 SCV001140263 likely pathogenic Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV004022223 SCV004933253 likely pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 7651740]. This variant is expected to disrupt protein structure [Myriad internal data].
GeneDx RCV004719814 SCV005326024 pathogenic not provided 2024-03-04 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation, lack of growth suppression ability, and dominant-negative effect (PMID: 7935394, 16861262, 30224644, 29979965, 12826609); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in an individual with breast cancer (PMID: 35264596); This variant is associated with the following publications: (PMID: 28243898, 15308588, 30224644, 31127692, 22492626, 8633021, 26085511, 15922892, 7935394, 10567903, 10761705, 15161705, 16861262, 29979965, 15510160, 32817165, 35264596, 12826609)

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.