ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.329G>A (p.Arg110His) (rs11540654)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000228299 SCV001429618 likely benign Li-Fraumeni syndrome 2020-08-11 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor.) In summary, TP53 c.329G>A (p.Arg110His) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4, BS3_Supporting, BS2_Supporting.
GeneDx RCV000589869 SCV000149628 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing This variant is denoted TP53 c.329G>A at the cDNA level, p.Arg110His (R110H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been observed in at least three individuals with breast cancer (Rath 2013, Tung 2016, Hauke 2018). TP53 Arg110His was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. This variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), and other functional studies have revealed growth suppression and apoptotic activities comparable to wild-type (Bergamaschi 2003, Kotler 2018). TP53 Arg110His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether TP53 Arg110His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115719 SCV000184511 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-30 criteria provided, single submitter clinical testing The p.R110H variant (also known as c.329G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 329. The arginine at codon 110 is replaced by histidine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially deficient transactivation capacity in yeast-based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9<span style="background-color:initial">). <span style="background-color:initial">It has been reported as a somatic mutation twice, and as a germline alteration <span style="background-color:initial">in a patient diagnosed with breast cancer at 32 years of age (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat<span style="background-color:initial">. 2007 Jun;28(6):622-9; <span style="background-color:initial">Rath MG et al. Breast Cancer Res<span style="background-color:initial">. Treat.<span style="background-color:initial"> 2013 May;139(1):193-8<span style="background-color:initial">). In addition, this alteration was detected in one cancer-free patient in a study examining prevalence of cancer gene variants in a healthy control population (<span style="background-color:initial">Bodian DL et al. PLoS ONE 2014; 9(4):e94554<span style="background-color:initial">). Two other alterations at this amino acid position, p.R110L and p.R110P, have been detected in individuals with a diagnosis of Li-Fraumeni Syndrome based on personal and family history (Rines RD et al. Carcinogenesis. <span style="background-color:initial">1998 Jun;19(6):979-84; Masciari S et al. Genet. Med. <span style="background-color:initial">2011 Jul;13(7):651-7). This amino acid position is not well conserved in available vertebrate species with histidine as the reference amino acid in several mammalian species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000228299 SCV000285188 uncertain significance Li-Fraumeni syndrome 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 110 of the TP53 protein (p.Arg110His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs11540654, ExAC 0.03%). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 23580068). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 127808). Experimental in vitro studies have shown that this missense change causes a very small effect on cellular sensitivity to cisplastin-induced apoptosis (PMID: 12726864) and partially affects the transcriptional transactivation function of the TP53 protein (PMID: 12826609). The clinical significance of these results is unknown. 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.
Counsyl RCV000409407 SCV000488218 uncertain significance Li-Fraumeni syndrome 1 2016-01-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589869 SCV000697440 uncertain significance not provided 2016-02-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115719 SCV000902812 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 110 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits normal activity in a yeast transactivation assay and cellular apoptosis assay (PMID: 12726864, 12826609) and does not show dominant negative effect or loss of function in human cell growth assay (PMID: 30224644). This variant has been reported in individuals affected with breast cancer (PMID: 23580068, 29522266). This variant has been identified in 13/282662 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589869 SCV001134867 uncertain significance not provided 2019-07-16 criteria provided, single submitter clinical testing
ITMI RCV000122182 SCV000086399 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115719 SCV000886720 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358219 SCV001553893 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The TP53 p.Arg110His variant was identified in 1 of 14548 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer or HER2+ breast cancer and was present in 3 of 23844 control chromosomes (frequency: 0.0001) from healthy individuals (Momozawa 2018, Rath 2014, Bodian 2014). The variant was also identified in dbSNP (ID: rs11540654) as "With Likely pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and three other submitters), and in LOVD 3.0 (2X). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 13 of 277020 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24008 chromosomes (freq: 0.00004), Latino in 3 of 34416 chromosomes (freq: 0.00009), European in 6 of 126568 chromosomes (freq: 0.00005), and East Asian in 3 of 18862 chromosomes (freq: 0.0002); it was not observed in the Other, Ashkenazi Jewish, Finnish, or South Asian populations. One study found that this variant had a similar effect on the modulation of cytotoxicity as compared to a control, suggesting a non-pathogenic role for this variant (Bergamaschi 2003). The p.Arg110 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer,) do not predict a difference in splicing. 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.

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