chr17-7676040-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS2BP4BS3_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.329G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 110 (p.Arg110His). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0728; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, BP4. (Bayesian Points: -4; VCEP specifications version 2.1; 1/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000123/MONDO:0018875/009
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251284Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135842
GnomAD4 exome AF: 0.0000630 AC: 92AN: 1460088Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 726324
GnomAD4 genome 0.0000591 AC: 9AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74458
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
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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. -
not provided Uncertain:3
The TP53 c.329G>A; p.Arg110His variant (rs11540654) has been previously reported in at least two individuals with a personal history of breast cancer who tested negative for pathogenic variation in numerous genes associated with hereditary breast cancer, including BRCA1 and BRCA2, though the identified p.Arg110His variant was not definitively determined to be causative(Rath 2013 and Hauke 2018). Early promoter transactivation studies indicate this variant results in a partially active TP53 protein (Kato 2003; IARC Database). However, subsequent functional analyses have demonstrated that this variant does not confer a significant growth advantage in cell culture models of TP53-mediated cellular proliferation (Bergamaschi 2003, Giacomelli 2018, Kotler 2018). These conclusions of a neutral effect on protein function are in line with computational models demonstrating that the arginine at codon 110 is weakly conserved (Alamut v.2.11; with several related species harboring a histidine at this position), and that the substituted histidine is a small physiochemical change from arginine. The p.Arg110His variant is found in the general population with an overall allele frequency of 0.005% (13/282,662 alleles) in the Genome Aggregation Database, and was found in an individual included in a healthy, unselected population (Bodian 2014). Post hoc analysis of these frequency estimates, in addition to observations from other cancer cohorts, has resulted in discrepant conclusions regarding pathogenicity. One study has suggested that this variant is likely to be pathogenic based on population frequency, though the authors specified that they established separate nonclinical classification criteria for research purposes (Andrade 2019), whereas two studies (one in direct critical response to Andrade et al) have concluded that this variant is more likely to be benign (Evans 2019 and Fortuno 2019). In reflection of the many conflicting pieces of information regarding the p.Arg110His variant, it should be noted that an FDA-recognized expert panel has concluded this variant is likely to be benign (ClinVar Variation ID: 127808). Based on the available information, we consider the clinical significance of this variant to be uncertain at this time. REFERENCES Andrade KC et al. Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis Hum Mutat. 2019 Jan;40(1):97-105. Bergamaschi D et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell. 2003 Apr;3(4):387-402. Bodian et al., Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. PLoS One. 2014 Apr 11;9(4):e94554. Evans et al., Concern regarding classification of germline TP53 variants as likely pathogenic. Hum Mutat. 2019 Jun;40(6):828-831. Fortuno et al., A quantitative model to predict pathogenicity of missense variants in the TP53 gene. Hum Mutat. 2019 Jun;40(6):788-800. Giacomelli AO et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet. 2018 Oct;50(10):1381-1387. Hauke J et al. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med. 2018 Apr;7(4):1349-1358. Kato S et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Kotler E et al. A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. Mol Cell. 2018 Jul 5;71(1):178-190.e8. Rath et al., Prevalence of germline TP53 mutations in HER2+ breast cancer patients. Breast Cancer Res Treat. 2013 May;139(1):193-8. -
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies are inconclusive: partially functional transactivation; growth suppression and apoptotic activities comparable to wild-type (Bergamaschi 2003, Kato 2003, Kotler 2018); Observed in individuals with breast cancer (Rath 2013, Tung 2016, Hauke 2018); This variant is associated with the following publications: (PMID: 16061860, 24728327, 24113472, 17062677, 26976419, 28446639, 21512767, 12826609, 22356895, 22228431, 26206375, 29979965, 14612556, 23243274, 23580068, 29522266, 21552135, 12726864, 30352134, 31016814, 30840781) -
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Li-Fraumeni syndrome 1 Uncertain:2
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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. -
not specified Uncertain:1Other:1
Variant summary: TP53 c.329G>A (p.Arg110His) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251284 control chromosomes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), suggesting that the variant is benign. c.329G>A has been reported in the literature in individuals in individuals with leukemia (Jeromin_2014, Winter_2021), head and neck cancer (Bergamaschi _2003, Vivenza_2012) and breast cancer (Boyault_2011, Rath_2013, Silwat-Pandt_2014, Tung_2016). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Several publications report mixed mixed results on the impact of the variant on protein function. These reports indicate no impact on expression, but transactivation experiments have ranged in their assessments from functionally abnormal to indistinguishable from wild-type (Doffe_2020, Raad_2021). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories and one expert panel reported the variant with conflicting assessments (7 classified it as VUS, 2 as likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -
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Li-Fraumeni syndrome Benign:2
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The NM_000546.6: c.329G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 110 (p.Arg110His). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007119 (84/1,180,010 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0728; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3_Supporting, BP4. (Bayesian Points: -4; VCEP specifications version 2.1; 1/16/2025). -
Malignant tumor of breast Uncertain:1
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. -
TP53-related disorder Uncertain:1
The TP53 c.329G>A variant is predicted to result in the amino acid substitution p.Arg110His. This variant has been reported in individuals with breast cancer (Rath et al. 2013. PubMed ID: 23580068; Tung et al. 2016. PubMed ID: 26976419, Table A2; Hauke et al. 2018. PubMed ID: 29522266, Table S2); however, no evidence was provided to support its pathogenicity. It was predicted to be likely benign using a quantitative model to predict pathogenicity of missense variants (Fortuno et al. 2019. PubMed ID: 30840781, Table S1). Another study reported this variant as likely benign after case control comparisons, and functional analysis evidence (Evans et al. 2019. PubMed ID: 31016814). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. In ClinVar, laboratories classify it is a variant of uncertain significance, and the ClinGen TP53 Variant Curation Expert Panel classifies it as likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127808/). While we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at