Submissions for variant NM_000546.6(TP53):c.313G>A (p.Gly105Ser)

dbSNP: rs1060501195

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492331	SCV000581123	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-03-17	criteria provided, single submitter	clinical testing	<span style="font-size:12px">The p.G105S variant (also known as c.313G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 313. The glycine at codon 105 is replaced by serine, an amino acid with similar properties.<span style="font-family:arial,sans-serif">This alteration is located in the functionally critical DNA binding domain and has shown a loss of transactivation activity in yeast based functional studies (Kato S et al. <span style="font-family:arial,sans-serif">Proc<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Natl<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Acad<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Sci USA<span style="font-family:arial,sans-serif">. 2003 Jul 8;100(14):8424-9). Although this specific alteration has not been reported in the literature, another alteration at this position (p.G105C) was reported in a family with classic Li-Fraumeni Syndrome, where the proband had three primary breast cancers by the age of 31, and a family history of early onset breast cancer and brain tumors (Bendig I et al., <span style="font-family:arial,sans-serif">Cancer Genet. <span style="font-family:arial,sans-serif">Cytogenet<span style="font-family:arial,sans-serif">.<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">2004 Oct; 154(1):22-6). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., <span style="font-family:arial,sans-serif">Science 1994 Jul; 265(5170):346-55). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT <span style="font-family:arial,sans-serif">in silico<span style="font-family:arial,sans-serif"> analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379190	SCV001576941	pathogenic	Li-Fraumeni syndrome	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 105 of the TP53 protein (p.Gly105Ser). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly105 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644, 30840781). 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: 428884). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (Invitae; external communications). This variant is not present in population databases (gnomAD no frequency).
Genome-Nilou Lab	RCV000492331	SCV002582410	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289669	SCV002583072	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University	RCV004003474	SCV004046833	likely pathogenic	Adrenal cortex carcinoma		no assertion criteria provided	clinical testing