Submissions for variant NM_000546.6(TP53):c.437G>A (p.Trp146Ter)

dbSNP: rs1206165503

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001022390	SCV001184119	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	The p.W146* pathogenic mutation (also known as c.437G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 437. This changes the amino acid from a tryptophan to a stop codon within coding exon 4. This alteration has been reported in individuals with early-onset and/or multiple cancer diagnoses, including a woman diagnosed with breast cancer at age 22 and in kindreds diagnosed with Li-Fraumeni syndrome (Wilson JR et al. J. Med. Genet. 2010 Nov;47:771-4; Wu CC et al. Hum. Genet. 2011 Jun;129:663-73; Melhem-Bertrandt A et al. Cancer 2012 Feb;118:908-13; Eccles DM et al. Ann. Oncol. 2016 Mar;27:467-73). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055632	SCV001220032	pathogenic	Li-Fraumeni syndrome	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp146*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Li Fraumeni syndrome (PMID: 20805372, 21305319, 21761402). ClinVar contains an entry for this variant (Variation ID: 634785). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001022390	SCV002582601	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290032	SCV002583163	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002290032	SCV004933079	pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
GeneDx	RCV005241401	SCV005888859	pathogenic	not provided	2024-09-16	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29979965, 25525159, 30720243, 35710434, 35734982, 34326862, 37937776, 21305319, 12509970, 15308588, 10656807, 11429705, 10567903, 15541116, 22768918, 26681682, 37304756, 39062707, 32164171, 27759562, 21761402, 20805372)
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785547	SCV000924119	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
deCODE genetics, Amgen	RCV002290032	SCV004022267	likely pathogenic	Li-Fraumeni syndrome 1	2023-07-21	no assertion criteria provided	research	The variant NM_000546.6:c.437G>A (chr17:7675175) in TP53 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University	RCV004001542	SCV004046828	likely pathogenic	Adrenal cortex carcinoma		no assertion criteria provided	clinical testing