Submissions for variant NM_000546.6(TP53):c.666G>T (p.Pro222=)

dbSNP: rs72661118

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162396	SCV000212719	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Invitae	RCV001085434	SCV000253314	likely benign	Li-Fraumeni syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000409816	SCV000489223	likely benign	Li-Fraumeni syndrome 1	2016-09-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162396	SCV000686759	likely benign	Hereditary cancer-predisposing syndrome	2015-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588456	SCV000697445	benign	not provided	2017-07-21	criteria provided, single submitter	clinical testing	Variant summary: The TP53 c.666G>T (p.Pro222Pro) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 12/277398 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000087 (11/126590). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398), suggesting this is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. Multiple publications have cited the variant as a somatic occurrence across varying cancers, however, germline analysis was not performed in these studies. A publication, Damineni_2014, does cite the variant, c.666G>C (p.Pro222Pro) as a germline occurrence in a BrC pt, however, limited information is provided (ie, no co-occurrence or cosegregation data and TP53 exons 5-9 were only assessed). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588456	SCV001134875	benign	not provided	2023-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000588456	SCV001940211	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29979965)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798376	SCV002042830	likely benign	Breast and/or ovarian cancer	2021-02-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162396	SCV002532701	likely benign	Hereditary cancer-predisposing syndrome	2021-01-10	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000162396	SCV002582549	likely benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000409816	SCV002582851	likely benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409816	SCV004017834	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.
PreventionGenetics, part of Exact Sciences	RCV003915186	SCV004734901	likely benign	TP53-related condition	2019-04-23	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Laboratory of Translational Genomics, National Cancer Institute	RCV000119374	SCV000154281	not provided	Neoplasm of ovary		no assertion provided	not provided