Submissions for variant NM_000546.6(TP53):c.736A>G (p.Met246Val)

dbSNP: rs483352695

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000161036	SCV000276627	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing	The p.M246V pathogenic mutation (also known as c.736A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 736. The methionine at codon 246 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in two members of a single family meeting Chompet criteria for TP53 genetic testing. Both the original patient, who was diagnosed with Wilm's tumor at age 2, and her mother, who was diagnosed with cervical cancer at age 30 and a glioma at age 35, were found to carry the alteration. In addition, although her brother did not have genetic testing, he was diagnosed with adrenal cancer at age 1 (Bardeesy N et al Nat. Genet. 1994 May;7(1):91-7). Furthermore, this alteration was identified in a 38-year-old woman with breast cancer and two of her first degree relatives with bilateral breast cancer and sarcoma (internal data). Functional analysis has shown this variant to have severely deficient transactivation capacity, and dominant negative characteristics in yeast based studies (Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis 2007 Feb;28(2):289-98; Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul 8;100(14):8424-9). Based on internal structural analysis, this variant sits in the DNA-binding domain and is anticipated to result in a significant decrease in structural stability and loss of functionality (Cho Y et al. Science 1994 Jul; 265(5170):346-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000460370	SCV000545351	pathogenic	Li-Fraumeni syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 246 of the TP53 protein (p.Met246Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with choroid plexus carcinoma, Wilm's tumor, cervical cancer, glioma cancer, breast cancer and/or prostate cancer (PMID: 8075648, 26534844, 28369373, 29946497). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 100815). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 1918170, 12826609, 17606709, 21343334, 28369373). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000161036	SCV002582464	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288585	SCV002583125	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000087173	SCV002774381	pathogenic	not provided	2021-07-30	criteria provided, single submitter	clinical testing	The variant has been reported in Li-Fraumeni syndrome and Li-Fraumeni-like families including individuals affected with breast/ovarian cancer and prostate cancer in the published literature (PMIDs: 8075648 (1994), 26534844 (2016), 29946497 (2018), and 32555031 (2021)). Functional studies have shown that this variant is severely deficient in activity and shows a dominant-negative effect (PMIDs: 12826609 (2003), 16861262 (2007), 17606709 (2007), 21343334 (2011), and 28369373 (2017)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV002288585	SCV004932929	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 28472496]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8075648, 26534844].
Richard Lifton Laboratory, Yale University School of Medicine	RCV000087173	SCV000120035	probable-pathogenic	not provided		flagged submission	not provided	Converted during submission to Likely pathogenic.
Richard Lifton Laboratory, Yale University School of Medicine	RCV000087173	SCV000155138	probable-pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785556	SCV000924128	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research