chr17-7674259-T-C
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BP4BS3BS4
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.704A>G variant in TP53 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 235 (p.Asn235Ser). This variant has been observed in at least 8 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; Internal lab contributor: SCV000185528.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been reported not to segregate with Li-Fraumeni syndrome in four affected family members from one family (BS4; PMID 17318340). Computational predictor scores (BayesDel = -0.0342; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 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_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BS4, BP4_Moderate. (Bayesian Points: -14; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000343/MONDO:0018875/009
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000224 AC: 34AN: 151756Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000179 AC: 45AN: 251484Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135912
GnomAD4 exome AF: 0.000250 AC: 366AN: 1461658Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 166AN XY: 727144
GnomAD4 genome AF: 0.000224 AC: 34AN: 151756Hom.: 0 Cov.: 30 AF XY: 0.000216 AC XY: 16AN XY: 74124
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:6
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In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 14559903, 10362336, 26483394, 20128691, 17606709, 7706467, 21343334, 25637381, 26086041, 17318340, 19367569, 24728327, 9067756, 9285560, 10432928, 21232794, 27194209, 25980754, 28861920, 29058119, 15580553, 29979965, 30352134, 29467486, 30262806, 31016814, 30840781, 31289210, 33300245) -
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TP53: BS3:Supporting, BS1, BS2 -
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not specified Uncertain:1Benign:4Other:1
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Variant summary: TP53 c.704A>G (p.Asn235Ser) results in a conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 251784 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Though the variant, c.704A>G, has been reported in the literature in individuals affected with various tumor types, it was also found in several healthy controls (de Andrade 2017, FLOSSIES database). Moreover, the variant was shown not to co-segregate with disease in at least one LFS family, who also carried a pathogenic splice site TP53 variant (van Hest 2007), suggesting that the variant of interest was not the cause of LFS in this family. Functional studies have shown this variant to have normal DNA binding properties and a well preserved transcriptional activity (>70% of normal activity), while the majority of known pathogenic TP53 variants have a transcriptional activity of <20% (Gonzalez 2011, Monti 2011, van Hest 2007, Soussi 2005). Additionally, immunohistochemical staining of tumors from carriers of the variant showed no expression of p53, while positive staining is commonly seen for pathogenic TP53 missense mutations (van Hest 2007). Nine other ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen TP53 Variant Curation Expert Panel) cite the variant as likely benign/benign (n=8) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign. -
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The p.Asn235Ser variant in TP53 is classified as Likely Benign because it has been identified in 0.03% (41/129118) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, although it has been reported in individuals with cancer (Diller 1995, Ponten 1997, Auer 1999, Huusko,1999), this variant was shown not to segregate with disease in at least 4 affected individuals from 1 family (van Hest 2007). In this family, the variant was identified in individuals with disease, who carried an additional pathogenic variant sufficient to explain their clinical presentation. The p.Asn235Ser variant has been reported in ClinVar (Variation ID: 127821). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein and in vitro functional studies provide additional evidence that this variant does not impact protein function (van Hest 2007). ACM/AMP Criteria applied: BS1_Supporting, BP4, BS4, BS3_Supporting -
Hereditary cancer-predisposing syndrome Benign: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. -
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Li-Fraumeni syndrome 1 Uncertain:1Benign:1
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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. -
Li-Fraumeni syndrome Benign:2
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The NM_000546.6: c.704A>G variant in TP53 is a missense variant predicted to cause substitution of asparagine by serine at amino acid 235 (p.Asn235Ser). This variant has been observed in at least 8 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; Internal lab contributor: SCV000185528.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been reported not to segregate with Li-Fraumeni syndrome in four affected family members from one family (BS4; PMID 17318340). Computational predictor scores (BayesDel = -0.0342; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 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_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BS4, BP4_Moderate. (Bayesian Points: -14; VCEP specifications version 2.0; 7/24/2024) -
Rhabdomyosarcoma Uncertain:1
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Breast and/or ovarian cancer Benign:1
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TP53-related disorder Benign:1
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). -
Squamous cell carcinoma of the head and neck Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at