ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.799C>T (p.Arg267Trp) (rs55832599)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130398 SCV000185257 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-30 criteria provided, single submitter clinical testing The p.R267W variant (also known as c.799C>T) is located in coding exon 7 of the TP53 gene. This alteration results from a C to T substitution at nucleotide position 799. The arginine at codon 267 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in breast cancer patients (Melhem-Bertrandt A et al. Cancer 2012 Feb;118(4):908-13; Stoltze U et al. PLoS ONE, 2018 Jan;13:e0190050) and in a female patient with myelodysplastic syndrome at age 52 (Villani A et al. Lancet Oncol., 2016 Sep;17:1295-305). It was also identified in two members of one family that met Li-Fraumeni syndrome (LFS) criteria (Llovet P et al. Fam. Cancer. 2017 Oct;16(4):567-575) and in two siblings with choroid plexus carcinomas (AlHarbi M et al. NPJ Genom Med. 2018 Dec 19;3:35). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a moderate dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional functional assays conducted in human tumor cell lines demonstrated a lack of transactivation activity, deficient DNA binding, and an inability to suppress cell growth in response to DNA damaging agents (Wang B et al. Cell Death Differ. 2014 Apr; 21(4):521-32; Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8). To date, this alteration has not been detected in any cases of classic Li-Fraumeni syndrome (LFS) in our clinical cohort (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R267W is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS, but rather leads to increased risk of developing a TP53-related cancer. Clinical correlation is advised.
GeneDx RCV000413074 SCV000491277 likely pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing The R267W variant has been published previously as a germline variant in a patient with breast cancer (Melhem-Bertrandt et al., 2012). However, no familial segregation studies have been published to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R267W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the DNA binding domain that is not conserved; however, in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown R267W abolishes the transactivation activity of the TP53 protein (Pekova et al., 2011). Therefore, we consider this variant to be likely pathogenic.
Invitae RCV000538977 SCV000629873 pathogenic Li-Fraumeni syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 267 of the TP53 protein (p.Arg267Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of Li-Fraumeni syndrome (PMID: 21761402, 27501770, 28573494, 29324801, 30588330). ClinVar contains an entry for this variant (Variation ID: 141764). Experimental studies have shown that this missense change disrupts TP53 transcriptional transactivation and results in decreased cellular apoptosis after stress (PMID: 16861262, 24076587, 12826609). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000130398 SCV000686775 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-22 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 267 the DNA binding domain 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 the mutant protein to be defective in transactivation, apoptosis induction, and cell growth control activity (PMID: 9627118, 12019170, 12826609, 24076587, 29979965). This variant has been reported in individuals affected with early-onset breast cancer, glioma, and soft-tissue sarcoma, who meet the Chompret criteria for Li-Fraumeni syndrome (PMID: 28573494, 2932480, Client internal data). This variant has also been reported in an unaffected individual with family history of Li-Fraumeni syndrome (PMID: 23484829). In one family meeting the Chompret criteria for Li-Fraumeni syndrome, this variant was observed in two heterozygous siblings affected with choroid plexus carcinomas and in their homozygous father who was healthy at age 39, indicating possibly low or variable penetrance of this variant (PMID 30588330). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763416 SCV000894153 likely pathogenic Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000538977 SCV001429670 likely pathogenic Li-Fraumeni syndrome 2020-02-28 criteria provided, single submitter clinical testing Data included in classification: UK family 1: Proband breast cancer at 42, mother breast cancer at 62 and melanoma, confirmed heterozygous for variant, maternal aunt leukaemia 30s, another maternal aunt colorectal ca 66 and lung ca 77, maternal grandmother lung ca 74 and maternal grandfather brain tumour (meets Chompret criteria). Literature family 1: MDS at 52, breast fibroadenoma, melanoma in situ, sessile serrated adenoma, subependymoma (all in 50s) (Villani et al, 2017, PMID: 27501770). Literature family 2: proband breast cancer at 31 and soft tissue sarcoma at 43, relative with breast cancer at 34 (meets Chompret criteria) (Lovett et al, 2017, PMID:28573494). Literature family 3: proband breast cancer at 43, sibling with oligodendroglioma at 31yrs (Stoltz et al, 2018, PMID:29324801) Literature family 4: AlHarbi et al 2018 (PMID: 30588330) proband CPC at 2, sister CPC at 14 months, paternal aunt (heterozygous for variant) liver cancer at 49, paternal great uncle CRC at 55, paternal great aunt and great grandmother brain tumours (meets Chompret criteria) (PS4_mod). Absent from gnomAD (PM2_sup). Deleterious on SIFT, Polyphen, AlignGVGD, Bayesdel 0.542, Revel 0.917 (PP3_mod). Functional data: Non-functional on Kato et al, 2003(PMID: 12826609); impaired function on Fulci et al, 2002: PMID: 12019170), Wang et al, 2013 (PMID: 24076587), Perez et al, 2016 (PMID: 27022024) (PS3_strong). Additional data (not included in classification): 5 classifications of likely pathogenic on ClinVar. Unaffected 38 year old homozygote (AlHarbi et al, 2018, PMID: 30588330). Wang et al, 2013 (PMID:23484829): variant reported but no family information available. AlHarbi et al 2018 (Stoltz et al, 2018 (PMID: 29324801) variant segregates with multiple relatives with cancer diagnoses, but also with unaffected relatives.
Institute of Medical Sciences, Banaras Hindu University RCV001255676 SCV001432241 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research

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