Submissions for variant NM_000546.6(TP53):c.388C>T (p.Leu130Phe)

dbSNP: rs863224683

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200055	SCV000254631	uncertain significance	Li-Fraumeni syndrome	2023-03-07	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 216466). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and/or breast cancer (PMID: 11332399, 18511570, 19468865). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 130 of the TP53 protein (p.Leu130Phe).
Ambry Genetics	RCV000571787	SCV000664438	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	The p.L130F pathogenic mutation (also known as c.388C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 388. The leucine at codon 130 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in a patient diagnosed with breast cancer at age 31y who has no reported family history of cancer, in a female patient diagnosed with sarcoma and rectal cancer at age 39y who has a family history of pancreatic cancer, and in a patient diagnosed with colorectal cancer at age 17y who has a family history of three paternal aunts with early-onset breast cancer diagnosed at ages 23y, 37y, and 40y (Chompret A et al. J Med Genet. 2001 Jan;38(1):43-7; Pinto C et al. Fam Cancer. 2009;8(4):383-90; Pinto P et al. Breast Cancer Res Treat. 2016 Sep;159(2):245-56). 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; Chompret A et al. J Med Genet. 2001 Jan;38(1):43-7). 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 alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271460	SCV002556050	uncertain significance	not specified	2022-06-21	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.388C>T (p.Leu130Phe) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250352 control chromosomes. The variant was reported in the IARC databse with 16 somatic and 2 germline occurrences. c.388C>T has been reported in the literature in the germline setting in an patient with breast cancer with 5 unaffected sisters (Chomprehet_2001), a patient with suspected LFS (Pinto_2009), a patient with germline predisposition syndrome without other clinical details (Martin_2021), and in a patient with colorectal cancer with a family history of breast cancer (Pinto_2016). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The IARC database reports the variant as being non-functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays by Kato et al. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Genome-Nilou Lab	RCV000571787	SCV002582094	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288816	SCV002582657	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000571787	SCV004360009	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 130 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant is non-functional in yeast transactivation assays (IARC database; PMID: 12826609), non-functional in human cell proliferation assays (PMID: 29979965), and exhibits dominant-negative effect and loss of function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with breast cancer at the age of 31 (PMID: 11332399), an individual affected with sarcoma and rectal cancer at the age of 39 with a family history of pancreatic cancer (PMID: 19468865), and an individual affected with colorectal cancer at the age of 17 with a family history of early-onset breast cancer (PMID: 27553368). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV002288816	SCV004933139	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-13	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].