TP53 c.380C>T, p.Ser127Phe
NM_000546.6:c.380C>T
COSMIC ID: COSM216414, COSM44226
Likely Pathogenic
The TP53 p.Ser127Phe variant demonstrates strong functional evidence of loss of function (PS3_Strong) and is absent from population databases (PM2_Supporting). No benign or other supporting criteria apply. One strong plus one supporting criterion meets Likely Pathogenic under ACMG/AMP and TP53-specific VCEP guidelines.
ACMG/AMP Criteria Applied
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.6:c.380C>T
Protein Change
S127F
Location
Exon 5
(Exon 5 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 127 in gene TP53
Alternate Identifiers
COSM216414, COSM44226
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.380C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
3 publications
Likely Pathogenic
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
3 Path
5 LP
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 127 of the TP53 protein (p.Ser127Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome and/or Li-Fraumeni syndrome (PMID: 32817165, 34240179; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182928). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16000567, 16322298, 29979965, 30224644). This variant disrupts the p.Ser127 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29470806; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
The p.S127F variant (also known as c.380C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 380. The serine at codon 127 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was detected in a cohort of 295 women considered at high risk for breast cancer (Guindalini RSC et al. Clin Cancer Res, 2019 Mar;25:1786-1794). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc Natl Acad Sci U S A, 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at the same codon, p.S127T (c.379T>A), has been shown to also have non-functional transactivation in yeast based assays, be deficient at growth suppression, and have a dominant negative effect (Ambry internal data; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as Likely pathogenic (5 clinical laboratories).
COSMIC ID
COSM216414, COSM44226
Recurrence
126 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 127 in gene TP53
Functional Summary
The TP53 S127F variant has been functionally characterized as inactivating. In vivo studies in yeast have shown a loss of transactivational activity, and in vitro studies in human cancer cell lines have demonstrated reduced growth suppression activity compared to the wildtype. These findings support a damaging effect on TP53 protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 5.17primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, canonical splice, initiation codon) following the TP53 decision tree. The c.380C>T (p.Ser127Phe) variant is a missense change, not predicted to cause a null allele. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a previously established pathogenic variant. No other variant yielding p.Ser127Phe has been classified as pathogenic. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies for confirmed de novo occurrences with appropriate clinical confirmation. No de novo evidence is available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines for TP53, PS3 at Strong strength applies when a variant is non-functional on Kato et al. data AND shows loss of function on another assay. The evidence shows loss of transactivation activity in yeast (Kato assay) and reduced growth suppression in human cancer cell lines (another functional assay). Therefore, PS3 is applied at Strong strength because the variant meets both non-functional and LOF requirements.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies based on proband points tally for Li-Fraumeni spectrum cancers. No such proband data or point total is reported for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants at TP53 hotspot codons 175, 245, 248, 249, 273, or 282. p.Ser127 is outside these codons. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for TP53, PM2 at Supporting strength applies when allele frequency is <0.00003 in gnomAD. The variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders with detected trans variants. TP53 is autosomal dominant and no phase data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop-loss variants. This is a missense variant. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies for missense at a residue with ≥1 TP53 pathogenic missense variants. No other pathogenic variants at codon 127 are documented by the VCEP. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. No de novo assumption or partial evidence exists. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies based on cosegregation in families. No familial segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies when a gene has a low rate of benign missense variation and missense are common mechanism. TP53 has many pathogenic missense variants and benign variation; PP2 is not recommended by VCEP. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 at Moderate or Supporting requires BayesDel and aGVGD thresholds or SpliceAI ≥0.2. BayesDel score is unavailable and computational predictions are mixed. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies for somatic observation patterns (clonal hematopoiesis) with VAF metrics. No such VAF data are provided. Therefore, PP4 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies for allele frequency ≥0.001 in gnomAD. The variant is absent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies for filtering AF ≥0.0003 but <0.001. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies for unrelated elderly female controls without cancer. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional assays show no LOF on Kato et al. and other assays. The variant shows LOF. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for lack of segregation in affected family members. No segregation data exist. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to Missense in gene where only truncating variants cause disease. TP53 disease is missense dominant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant for autosomal dominant. No such evidence. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame deletions in repetitive regions. This is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 at Moderate or Supporting requires BayesDel thresholds and SpliceAI <0.2. BayesDel is unavailable and in silico predictions are mixed. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant found in a case with an alternate molecular cause. No alternate cause reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports benign without data. No such benign report. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous variants with no splicing impact. This variant is missense. Therefore, BP7 is not applied.