Submissions for variant NM_000546.6(TP53):c.91G>A (p.Val31Ile)

gnomAD frequency: 0.00004  dbSNP: rs201753350

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000122173	SCV000149651	likely benign	not specified	2017-10-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000123100	SCV000166401	likely benign	Li-Fraumeni syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115742	SCV000187523	likely benign	Hereditary cancer-predisposing syndrome	2020-09-22	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.
Illumina Laboratory Services, Illumina	RCV000409871	SCV000407074	likely benign	Li-Fraumeni syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl	RCV000409871	SCV000487895	uncertain significance	Li-Fraumeni syndrome 1	2015-12-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586196	SCV000697455	benign	not provided	2017-04-27	criteria provided, single submitter	clinical testing	Variant summary: The c.91G>A (p.Val31Ile) in TP53 gene is a missense change that involves a conserved nucleotide. The variant is located just outside of the p53 transactivation domain. Although 4/5 in silico tools predict benign outcome, in the functional studies the variant displayed moderately reduced cell proliferation suppressing activity as well as transcriptional activity on p21 (CDKN1A) and MDM2 promoters, but not on the BAX promoter compared to wt-tp53 (Yamada, 2007). In addition, it is also classified as functionally competent variant in TP53 database. The variant is present in the large control population dataset of ExAC and gnomAD at a similar frequencies of 0.00026 (31/118406 and 58/275552 chromosomes tested, respectively), predominantly in individuals of East Asian descent (0.00353; 30/ 8498 chromosomes and 58/18782 chromosomes tested) including one homozygote. These frequencies exceed the maximal expected frequency of a pathogenic allele (0.000047) in this gene. The variant has been reported in several cancer-affected individuals without evidence for causality (Toguchida, 1992; Lee, 2010; Yamada, 2007; Yamaguchi, 2016) and is generally regarded as a polymorphism. In addition, one individual dx with thyroid carcinoma tested positive for BRAF V600E, further supporting benign outcome of the variant of interest. The variant was also identified in one internal LCA specimen in co-occurrence with a known pathogenic variant in MSH6 c.4068_4071dupGATT (p.K1358fs*2). Lastly, multiple reputable databases/clinical laboratories cite the variant with classification of Likely Benign. Taking all lines of evidence into consideration, this variant has been classified as Benign.
Color Diagnostics, LLC DBA Color Health	RCV000115742	SCV000910670	likely benign	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000409871	SCV001140270	likely benign	Li-Fraumeni syndrome 1	2020-05-15	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030741	SCV001193757	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586196	SCV002046225	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115742	SCV002532723	likely benign	Hereditary cancer-predisposing syndrome	2021-11-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409871	SCV004017840	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492490	SCV004239793	likely benign	Breast and/or ovarian cancer	2023-02-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945046	SCV004758411	likely benign	TP53-related disorder	2019-12-12	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).
ITMI	RCV000122173	SCV000086388	not provided	not specified	2013-09-19	no assertion provided	reference population
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000409871	SCV000267534	likely pathogenic	Li-Fraumeni syndrome 1	2016-03-18	flagged submission	reference population