17-7676532-G-A
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000546.6(TP53):c.63C>T(p.Asp21Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,614,004 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00025 ( 4 hom. )
Consequence
TP53
NM_000546.6 synonymous
NM_000546.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0590
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.62).
BP6
Variant 17-7676532-G-A is Benign according to our data. Variant chr17-7676532-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184112.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=6}.
BP7
Synonymous conserved (PhyloP=0.059 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000138 (21/152248) while in subpopulation SAS AF= 0.00435 (21/4830). AF 95% confidence interval is 0.00291. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 21 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000138 AC: 21AN: 152130Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000535 AC: 134AN: 250398Hom.: 2 AF XY: 0.000685 AC XY: 93AN XY: 135722
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GnomAD4 exome AF: 0.000250 AC: 366AN: 1461756Hom.: 4 Cov.: 35 AF XY: 0.000369 AC XY: 268AN XY: 727172
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GnomAD4 genome 0.000138 AC: 21AN: 152248Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74440
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TP53 p.Asp21= variant was identified in 4 of 658 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer (Ginsburg 2009, Holstege 2009, Lee 2010). The variant was also identified in dbSNP (ID: rs1800369) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Integrated Genetics/Laboratory Corporation of America; as likely benign by Color Genomics, Ambry Genetics), and in IARC TP53 (2x). The variant was not identified in the COGR, or LOVD 3.0 databases. The variant was identified in control databases in 136 of 245170 chromosomes (2 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 136 of 30680 chromosomes (freq: 0.004), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Asp21= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 23, 2017 | Variant summary: The TP53 c.63C>T (p.Asp21Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 73 of 119254 control chromosomes (2 homozygotes), but was observed exclusively in the South Asian subpopulation at a frequency of 0.004463 (73/16356; 2 homozygotes). This frequency is about 112 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398), strongly suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant has been identified in breast cancer and lung cancer patients without evidence for pathogenicity (Holstege_Can Res_2009; Ginsburg_Fam Cancer_2009; Lee_JCMS_2010). Immunostaining studies in breast cancer tissue showed that TP53 was present in all cells analyzed, suggesting the variant does not affect expression (Holstege_Can Res_2009). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations, including uncertain significance, likely benign and benign. Taken together, this variant is classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 20, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2014 | 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. - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 04, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 28, 2015 | - - |
Li-Fraumeni syndrome Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 19, 2023 | - - |
Familial cancer of breast Benign:1
| Likely benign, criteria provided, single submitter | case-control | Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo | - | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at