NM_000546.6:c.666G>T
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_000546.6(TP53):c.666G>T(p.Pro222Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P222P) has been classified as Benign.
Frequency
Consequence
NM_000546.6 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251280Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135818
GnomAD4 exome AF: 0.000105 AC: 153AN: 1461722Hom.: 0 Cov.: 34 AF XY: 0.000105 AC XY: 76AN XY: 727164
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74466
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:4
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This alteration is classified as 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. -
Li-Fraumeni syndrome 1 Benign:3
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This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
not provided Benign:3
This variant is associated with the following publications: (PMID: 29979965) -
Variant summary: The TP53 c.666G>T (p.Pro222Pro) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 12/277398 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000087 (11/126590). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398), suggesting this is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. Multiple publications have cited the variant as a somatic occurrence across varying cancers, however, germline analysis was not performed in these studies. A publication, Damineni_2014, does cite the variant, c.666G>C (p.Pro222Pro) as a germline occurrence in a BrC pt, however, limited information is provided (ie, no co-occurrence or cosegregation data and TP53 exons 5-9 were only assessed). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -
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Li-Fraumeni syndrome Benign:2
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not specified Benign:2
The p.Pro222Pro variant in TP53 is classified as likely benign because it does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact on splicing. It has been identified in 0.009% (11/129078) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BP4, BP7. -
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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). -
Ovarian neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at