Submissions for variant NM_000546.6(TP53):c.412G>C (p.Ala138Pro)

dbSNP: rs28934875

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461233	SCV000545311	pathogenic	Li-Fraumeni syndrome	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 138 of the TP53 protein (p.Ala138Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome-related cancers (adrenocortical carcinoma, rhabdomyosarcoma, chondrosarcoma, breast cancer) (PMID: 9569035, 17567834). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12376). 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, 15548685, 17606709, 19958544, 21343334). This variant disrupts the p.Ala138 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 22507745, 32552660), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002326677	SCV002627174	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-23	criteria provided, single submitter	clinical testing	The p.A138P pathogenic mutation (also known as c.412G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 412. The alanine at codon 138 is replaced by proline, an amino acid with highly similar properties. This alteration has been identified in a family meeting Li-Fraumeni syndrome criteria (Sedlacek Z et al. Br J Cancer, 1998 Apr;77:1034-9) and also in two related individuals with medulloblastoma (Waszak SM et al. Lancet Oncol, 2018 06;19:785-798). 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 and 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV004719641	SCV005324866	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (PMID: 12826609, 21343334, 29979965, 30224644); 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: 17606709, 30840781, 15548685, 18765419, 20118236, 25847421, 30224644, 21343334, 19958544, 17567834, 25584008, 29753700, 29979965, 15510160, 9569035, 12826609)
OMIM	RCV000013175	SCV000033422	pathogenic	Li-Fraumeni syndrome 1	1998-04-01	no assertion criteria provided	literature only