Submissions for variant NM_000546.6(TP53):c.1149C>T (p.Leu383=)

gnomAD frequency: 0.00004  dbSNP: rs373710656

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162452	SCV000212805	likely benign	Hereditary cancer-predisposing syndrome	2014-08-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206094	SCV000261005	likely benign	Li-Fraumeni syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000410097	SCV000487941	likely benign	Li-Fraumeni syndrome 1	2015-12-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162452	SCV000537510	likely benign	Hereditary cancer-predisposing syndrome	2015-12-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000989696	SCV001140235	likely benign	Squamous cell carcinoma of the head and neck	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001711320	SCV001940215	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001711320	SCV002047298	likely benign	not provided	2021-01-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000162452	SCV002582198	likely benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000410097	SCV002582761	likely benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410097	SCV004017851	benign	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CeGaT Center for Human Genetics Tuebingen	RCV001711320	SCV004184643	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	TP53: BP4, BP7
All of Us Research Program, National Institutes of Health	RCV000206094	SCV004823713	likely benign	Li-Fraumeni syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354955	SCV001549689	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The TP53 p.Leu383= variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was also identified in dbSNP (ID: rs373710656) as "With Likely benign allele" and ClinVar (classified as likely benign by Invitae, Counsyl, Ambry Genetics and Color). The variant was identified in control databases in 9 of 246266 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 8 of 111716 chromosomes (freq: 0.00007) and Latino in 1 of 33582 chromosomes (freq: 0.00003), while it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Other, or South Asian populations. The p.Leu383= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.