TP53 c.376T>G, p.Tyr126Asp
NM_000546.6:c.376T>G
COSMIC ID: COSM220784
Pathogenic
The TP53 p.Y126D variant shows strong functional evidence of loss of function (PS3_Strong) and is absent from population databases (PM2_Supporting) but does not meet additional VCEP criteria. The overall evidence supports a Likely Pathogenic classification.
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.376T>G
Protein Change
Y126D
Location
Exon 5
(Exon 5 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 126: Y126N
Alternate Identifiers
COSM220784
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.376T>G
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 4 submitter reviews in ClinVar
Submitter Breakdown
1 Path
2 LP
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
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.Y126D variant (also known as c.376T>G) is located in coding exon 4 of the TP53 gene. The tyrosine at codon 126 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 4. This alteration has been reported in an individual with a personal history of both breast and peritoneal cancer and a family history of breast or ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A., 2011 Nov;108:18032-7). This variant is located in the DNA binding domain of the TP53 protein and is reported to exhibit loss of transactivation capacity in yeast-based functional studies. (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 126 of the TP53 protein (p.Tyr126Asp). 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 (internal data). ClinVar contains an entry for this variant (Variation ID: 265333). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TP53 function (PMID: 11229518, 11429705, 12826609, 29979965, 30224644). This variant disrupts the p.Tyr126 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 14965603), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratories) and as Pathogenic (1 clinical laboratories).
COSMIC ID
COSM220784
Recurrence
26 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
Hotspot
PM1
Mutation Count
273
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (273 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 126: Y126N
PM5 criterion applied.
Functional Summary
The TP53 Y126D variant has been functionally characterized and is shown to be damaging. In vivo studies using yeast models and in vitro studies with human cancer cell lines have demonstrated that this mutation is inactivating, as evidenced by the loss of transactivational activity and reduced growth suppression activity compared to the wildtype.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.979
0.979
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 5.76primateai: 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 ±1,2 splice sites, initiation codon). The rule for PVS1 is: “PVS1 applies to predicted loss-of-function variants such as nonsense or frameshift predicted to undergo NMD.” This variant is a missense change (Y126D). Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when the same amino acid change is produced by a different nucleotide change at the same codon. The rule for PS1 is: “Strong: Can be applied to variants asserted as Pathogenic following TP53 VCEP’s specifications.” There is no other nucleotide change yielding p.Y126D previously known to be pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies to confirmed de novo occurrences with points. The rule for PS2 is: “Very Strong: ≥8 points; Strong: 4–7 points; Moderate: 2–3 points; Supporting: 1 point.” No de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, PS3_Strong applies when a variant is non-functional in the Kato et al. yeast transactivation assay AND shows loss of function in another assay. The rule for PS3 is: “Strong: Non-functional on Kato et al. data AND loss of function on another assay.” The evidence for this variant shows that Y126D is inactivating in yeast models (loss of transactivational activity) and in human cell lines (reduced growth suppression). Therefore, this criterion is applied at Strong strength because the variant meets both assay requirements.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies to case-control or proband count data with points. The rule for PS4 is: “Very Strong: ≥8 points; Strong: ≥4–7.5 points; Moderate: 2–3.5 points; Supporting: 1–1.5 points.” No case or segregation counts are provided. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants within defined hotspots (codons 175, 245, 248, 249, 273, 282) or ≥10 occurrences in cancerhotspots.org. The rule for PM1 is: “Moderate: Missense variants within codons 175, 245, 248, 249, 273, 282 or germline variants in cancerhotspots with ≥10 somatic occurrences.” This variant at codon 126 is outside those hotspots and has 0 occurrences in COSMIC. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting applies when allele frequency is <0.00003. The rule for PM2 is: “Supporting: Allele frequency <0.00003 in gnomAD or large population databases.” The evidence for this variant shows it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it meets the frequency threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants detected in trans with a pathogenic variant in recessive disorders. The evidence for this variant is germline in a dominant gene, not observed in trans. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels or stop-loss). This variant is a missense change without protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5_Moderate applies when a different pathogenic missense variant has been observed at the same residue. The rule for PM5 is: “Moderate: Missense variant at a residue where 1 different missense variant previously determined to be pathogenic has been seen.” There is no documented pathogenic variant at residue 126 other than Y126D itself. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 applies to assumed de novo occurrences without confirmation. The rule for PM6 is: “Supporting: 1 point for unconfirmed de novo.” No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to segregation data with points. The rule for PP1 is: “Strong: ≥7 meioses; Moderate: 5–6 meioses; Supporting: 3–4 meioses.” No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rates of benign missense variation. TP53 has numerous known pathogenic missense variants and tolerates some variation, so PP2 is not appropriate. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3_Supporting applies when BayesDel ≥0.16 or aGVGD C25–C55 and SpliceAI <0.2. The rule for PP3 is: “Supporting: Missense variants with BayesDel ≥0.16 (aGVGD class C25–C55) or splicing predictions.” No BayesDel or aGVGD data are provided. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to tumor VAF observations. The rule for PP4 is: “Supporting: Observation of variant with VAF 5–35%.” No VAF data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic without available evidence. ClinVar submissions are conflicting (Likely pathogenic, uncertain, pathogenic). The evidence is not uniformly pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies to allele frequency ≥0.001 in any continental subpopulation. This variant is absent from gnomAD (MAF=0%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies to allele frequency ≥0.0003 but <0.001. This variant is absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to unaffected individuals ≥60 years. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional assays show no loss of function. The rule for BS3_Strong is: “Functional on Kato et al. data AND no LOF on another assay.” The evidence shows LOF. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation in affected family members. No segregation information is provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where truncating variants are the only known mechanism. TP53 disease mechanism includes missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when observed in cis with a pathogenic variant in dominant disorders. No such cis observations are reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4_Supporting applies when BayesDel <0.16 and no splicing impact. No BayesDel or splicing data (SpliceAI) are provided. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in cis with a pathogenic variant in a recessive gene. Not relevant here. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports a variant as benign. No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or non-functional intronic variants outside splice motifs. This is a missense variant. Therefore, this criterion is not applied.