Submissions for variant NM_000546.6(TP53):c.731G>A (p.Gly244Asp)

dbSNP: rs985033810

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413969	SCV000491278	pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	Reported in an individual with breast cancer (PMID: 34196900); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25637035, 27146902, 25525159, 9524109, 12909720, 16861262, 8633021, 15825182, 27196127, 24481001, 22178590, 19367287, 23939625, 16494995, 28222664, 28592622, 29413759, 28100260, 28945843, 32817165, 29979965, 29489754, 30076369, 29070607, 30287823, 30720243, 30840781, 34529667, 31105275, 30224644, 33309985, 36243179, 21343334, 32980694, 34273903, 15510160, 34196900)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477083	SCV000545270	pathogenic	Li-Fraumeni syndrome	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 244 of the TP53 protein (p.Gly244Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer, colon cancer, and melanoma (PMID: 16494995, 29470806; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372785). Invitae Evidence Modeling incorporating data from in vitro 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: 12826609, 16494995, 16861262, 21343334, 22319594, 29979965, 30224644). This variant disrupts the p.Gly244 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18511570, 18628487, 24307375, 25925845, 26818906). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000561866	SCV000667184	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-31	criteria provided, single submitter	clinical testing	The p.G244D pathogenic mutation (also known as c.731G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 731. The glycine at codon 244 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in a Brazilian individual diagnosed with breast cancer at 40 years old and colorectal cancer (age unspecified) with a family history of early-onset bone cancer, breast cancer, sarcoma, and cancer of the female genital organs (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102). This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170:189-196). This variant has also been reported in children with Li-Fraumeni syndrome-related cancers (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180; Grobner S et al. Nature. 2018 03;555(7696):321-327). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression has a dominant negative effect (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). In addition, two alterations at this same position (p.G244S and p.G244V) have been identified in individuals meeting Chompret criteria (Krutilkova V et al. Eur J Cancer. 2005 Jul;41(11):1597-603; Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV000561866	SCV002582467	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288986	SCV002583128	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000413969	SCV004026179	likely pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing	PS4, PP3, PM2_SUP, PS3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000477083	SCV004848117	likely pathogenic	Li-Fraumeni syndrome	2018-01-17	criteria provided, single submitter	clinical testing	The p.Gly244Asp variant in TP53 has been reported in 4 individuals with TP53-associated cancers (IARC TP53 Database: http://p53.iarc.fr, Achatz 2007, Oden-Gangloff 2009, Zeki 2013) and segregated with disease in 5 affected relatives from 1 family (Achatz 2007). This variant was absent from large population studies, but has been reported in ClinVar, as both a germline and somatic variant (Variation ID: 372785). Amino acid position 244 is a known TP53 mutation hotspot, with several different variants, including p.Gly244Ser and p.Gly244Val, that have been reported in individuals with TP53-associated cancers (Oden-Gangloff 2009, Zeki 2013, Watson 2014, Arcand 2015, Hu 2016, Krutilkova 2005, Monti 2011). In vitro functional studies provide some evidence that the p.Gly244Asp variant may impact protein function (Kato 2003, Monti 2011, Paget 2012). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly244Asp variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PS3_Moderate; PS4_Moderate; PP1_Moderate; PP3.
Myriad Genetics, Inc.	RCV002288986	SCV004932868	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: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785537	SCV000924109	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Laboratory for Genotyping Development, RIKEN	RCV003168599	SCV002758169	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research