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TP53c.623A>CUncertain significance
Print report
Variant interpretation report

TP53 c.623A>C, p.Asp208Ala

NM_000546.5:c.623A>C NP_000537.3:p.(Asp208Ala) Missense · exon 6 View identifiers
Classification
Uncertain significance

Variant description:

The TP53 NM_000546.5:c.623A>C (NP_000537.3:p.(Asp208Ala)) missense variant has previously been reported in somatic cancers (COSMIC; COSV106384816, n = 1 time), and lies in a statistically significant hotspot (cancerhotspots.org). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TP53

TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stress such as DNA damage by switching on genes that trigger cell cycle arrest, DNA repair, senescence, or programmed cell death. In healthy cells, p53 is kept at low levels by constant degradation, but stress signals stabilize and activate it to protect against damaged cells surviving and dividing. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a condition marked by a high risk of developing multiple cancers at a young age. TP53 is the most commonly mutated gene across human cancers, and loss of its normal function promotes tumor growth, spread, drug resistance, and genomic instability.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen TP53 VCEP v2.4. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, giving observed allele frequency 0 versus the <0.003% PM2 threshold.

PP3Moderate
PP3 · moderate

Met at moderate strength: the VCEP table pre-assigns PP3_moderate for c.623A>C with BayesDel 0.596355 (Class C65).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PM2 supporting (+1) plus PP3 moderate (+2) total 3 points under the TP53 Expert Panel's Version 2.4 framework.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
REVEL score
0.931 recorded score

Recorded REVEL score: 0.931. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 →
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV106384816, n = 1 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 5 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM3 and BP2 were adjudicated only under the ClinGen TP53 VCEP v2.4 specification; both are explicitly marked not applicable for this VCEP.

Met · 2

PM2 SupportingVCEPMet at supporting: the variant is absent from gnomAD v2.1 and v4.1, giving observed allele frequency 0 versus the <0.003% PM2 threshold. Details ▾Hide ▴
Reasoning

The TP53 VCEP applies PM2 only at supporting strength when the allele frequency is less than 0.00003 (0.003%) in gnomAD or another large sequenced population. The variant is absent from the default all-comers gnomAD v4.1 and gnomAD v2.1 datasets, therefore its observed allele frequency is 0 in those queried datasets and below 0.00003. The VCEP does not require a non-cancer or exome-only subset for this criterion; the available non-cancer queries are concordantly absent but are not used instead of the default all-comers evidence.

VCEP rule
This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population.
Evidence considered
  • ClinGen TP53 VCEP v2.4 PM2 rule: apply at supporting level when allele frequency is <0.00003 (0.003%) in gnomAD or another large sequenced population.
  • gnomAD v2.1 all-comers exome query for 17-7578226-T-G: absent; observed allele frequency 0 in the queried dataset.
  • gnomAD v4.1 all-comers query for chr17-7674908-T-G: absent; observed allele frequency 0 in the queried dataset.
  • gnomAD v2.1 non-cancer and v3.1 non-cancer queries were also absent, but the VCEP does not specify those subsets for PM2.
Still missing
  • The records provide absence calls but not total allele counts or ancestry-specific allele counts; no multiple-allele ancestry exception is triggered by the absent result.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PP3 ModerateVCEPMet at moderate strength: the VCEP table pre-assigns PP3_moderate for c.623A>C with BayesDel 0.596355 (Class C65). Details ▾Hide ▴
Reasoning

The variant is a missense change, NM_000546.5:c.623A>C (p.Asp208Ala/p.D208A). The governing TP53 Supplementary Table S2 contains the exact row c.623A>C, p.Asp208Ala, Class C65, BayesDel 0.596355, and pre-assigns PP3_moderate. That VCEP pre-assignment is controlling. The case's SpliceAI maximum delta score is 0.01, below the VCEP's no-predicted-splicing threshold of 0.2, so there is no splice-effect conflict with the missense PP3 assignment.

VCEP rule
**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants)_ aGVGD Class C65 and BayesDel score ≥ 0.16
Evidence considered
  • PP3-BP4-codes.xlsx, Supplementary Table S2 exact row: c.623A>C | p.Asp208Ala | Class C65 | BayesDel 0.596355 | PP3_moderate | 0.01.
  • The VCEP table's exact pre-assigned PP3_moderate code is applied directly and outranks an independent recalculation.
  • SpliceAI case result: DS_AG 0.0, DS_AL 0.002, DS_DG 0.0, DS_DL 0.01; maximum delta score 0.01.
Still missing
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt; the flowchart provides general rules rather than a variant row.
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; that file covers single amino acid in-frame deletions, not this missense variant.
  • The p.D208A notation was not found in PP3-BP4-codes.xlsx.txt, although the exact c.623A>C/p.Asp208Ala row was found.
Sources
cspec ↗vcep_pp3_bp4_codes ↗spliceai ↗

Not met · 5 · evaluated, threshold not reached

PS3 VCEPNot met: the governing D208A row assigns No evidence, with only 1 of 3 available non-Kato assays showing LOF and no qualifying Moderate or Supporting path. Details ▾Hide ▴
Reasoning

The governing TP53 Functional-worksheet.xlsx Supplementary Table S3 row for D208A reports Kato: Non-functional; Funk: noLOF; Giacomelli: LOF; Kotler: noLOF; Kawaguchi: NA; preliminary functional code: No evidence. The TP53 PS3 Strong path requires non-functional Kato data and LOF by the majority of other eligible assays; the available non-Kato assays include only one LOF result out of three (Giacomelli), so that path is not met. The PS3 Moderate path requires partially functional Kato data, which is not reported, and the PS3 Supporting path requires abnormal Kawaguchi data, which is NA. The governing worksheet therefore pre-assigns no PS3 code. The functional flowchart contains no variant-specific D208A, p.Asp208Ala, or c.623A>C row; its eligible-study list was consulted, while the worksheet row is the governing variant-specific assignment.

VCEP rule
Non-functional on Kato et al. data **AND** loss of function (LOF) by the majority of other eligible assays ... Partially functional on Kato et al. data **AND** loss of function (LOF) by the majority of other available assays ... Non-functional on Kato et al. data **AND** abnormal on Kawaguchi et al. data regardless of other assays
Evidence considered
  • Functional-worksheet.xlsx, Supplementary Table S3, row D208A: Kato class Non-functional; Funk class noLOF; Giacomelli class LOF; Kotler class noLOF; Kawaguchi class NA; preliminary functional code No evidence.
  • Flowchart-for-application-of-functional-rule-codes.pdf, page 1: eligible functional studies include Kato, Funk, Giacomelli, Kotler, and Kawaguchi.
  • PMID:12826609 was reviewed as the Kato assay source; the paper extract reports a yeast-based transactivation study but does not explicitly mention D208A, so the variant-specific Kato result is taken from the VCEP worksheet row.
Still missing
  • Flowchart-for-application-of-functional-rule-codes.pdf was searched for c.623A>C, p.Asp208Ala, and p.D208A; it contains no variant-specific entry.
Sources
vcep_functional_worksheet ↗vcep_flowchart_for_application_of_functional_rule_codes ↗cspec ↗PMID:12826609 ↗
BA1 VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, so no qualifying ancestry-group FAF reaches the 0.1% BA1 threshold. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires a filtering allele frequency (FAF) of at least 0.001 (0.1%) in a qualifying continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles present. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no qualifying FAF reaches the BA1 threshold. The available records do not provide ancestry-specific denominators or allele-balance data, but absence is sufficient to exclude a stand-alone benign frequency threshold.

VCEP rule
Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ("allele balance" in gnomAD) below 0.35.
Evidence considered
  • ClinGen TP53 VCEP v2.4 BA1 rule: qualifying ancestry-group FAF must be ≥0.001 (0.1%), with ≥2,000 alleles tested and at least 2 alleles present.
  • gnomAD v2.1 all-comers exome query for 17-7578226-T-G: absent.
  • gnomAD v4.1 all-comers query for chr17-7674908-T-G: absent.
Still missing
  • Ancestry-specific FAF denominators and allele-balance data are not available, although they cannot establish BA1 for an absent variant.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, so no qualifying ancestry-group FAF lies between 0.03% and 0.1%. Details ▾Hide ▴
Reasoning

The TP53 VCEP requires a qualifying ancestry-group FAF of at least 0.0003 but less than 0.001, with at least 2,000 alleles tested and at least 2 variant alleles present. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no qualifying FAF falls within the BS1 interval. The available records do not provide ancestry-specific denominators or allele-balance data, but absence cannot support a benign frequency threshold.

VCEP rule
Filtering allele frequency (FAF) of ≥ 0.0003 but < 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ("allele balance" in gnomAD) below 0.35.
Evidence considered
  • ClinGen TP53 VCEP v2.4 BS1 rule: qualifying ancestry-group FAF must be ≥0.0003 but <0.001, with ≥2,000 alleles tested and at least 2 alleles present.
  • gnomAD v2.1 all-comers exome query for 17-7578226-T-G: absent.
  • gnomAD v4.1 all-comers query for chr17-7674908-T-G: absent.
Still missing
  • Ancestry-specific FAF denominators and allele-balance data are not available, although they cannot establish BS1 for an absent variant.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 VCEPNot met: the governing D208A row assigns No evidence because Kato is non-functional and Giacomelli reports LOF. Details ▾Hide ▴
Reasoning

The governing TP53 Functional-worksheet.xlsx Supplementary Table S3 row for D208A reports Kato: Non-functional; Funk: noLOF; Giacomelli: LOF; Kotler: noLOF; Kawaguchi: NA; preliminary functional code: No evidence. The TP53 BS3 Strong path requires functional Kato data and no LOF by the majority of available eligible assays, but Kato is non-functional. The BS3 Supporting path requires partially functional Kato data and no LOF by all available assays, but Kato is non-functional and Giacomelli is LOF. The governing worksheet therefore pre-assigns no BS3 code. The functional flowchart contains no variant-specific D208A, p.Asp208Ala, or c.623A>C row; its eligible-study list was consulted, while the worksheet row is the governing variant-specific assignment.

VCEP rule
Functional on Kato et al. data **AND** no loss of function (LOF) by the majority of available eligible assays ... Partially functional on Kato et al. data **AND** no evidence of loss of function (LOF) by **all** available assays
Evidence considered
  • Functional-worksheet.xlsx, Supplementary Table S3, row D208A: Kato class Non-functional; Funk class noLOF; Giacomelli class LOF; Kotler class noLOF; Kawaguchi class NA; preliminary functional code No evidence.
  • Flowchart-for-application-of-functional-rule-codes.pdf, page 1: eligible functional studies include Kato, Funk, Giacomelli, Kotler, and Kawaguchi.
  • PMID:12826609 was reviewed as the Kato assay source; the paper extract reports a yeast-based transactivation study but does not explicitly mention D208A, so the variant-specific Kato result is taken from the VCEP worksheet row.
Still missing
  • Flowchart-for-application-of-functional-rule-codes.pdf was searched for c.623A>C, p.Asp208Ala, and p.D208A; it contains no variant-specific entry.
Sources
vcep_functional_worksheet ↗vcep_flowchart_for_application_of_functional_rule_codes ↗cspec ↗PMID:12826609 ↗
BP4 VCEPNot met: BP4 is explicitly barred for the VCEP Class C65 row, despite BayesDel 0.596355 and SpliceAI maximum delta 0.01. Details ▾Hide ▴
Reasoning

The variant is a missense change and the VCEP provides a missense BP4 path requiring BayesDel below 0.16 and no predicted splicing impact, but explicitly excludes Class C65 variants from BP4. The exact VCEP table row classifies c.623A>C as Class C65 with BayesDel 0.596355 and assigns PP3_moderate, so BP4 cannot be applied despite the SpliceAI maximum delta of 0.01 being below 0.2.

VCEP rule
**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants):_ BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI < 0.2)
Evidence considered
  • PP3-BP4-codes.xlsx, Supplementary Table S2 exact row: c.623A>C | p.Asp208Ala | Class C65 | BayesDel 0.596355 | PP3_moderate | 0.01; no BP4 code is assigned.
  • The VCEP missense BP4 rule's Class C65 exception applies directly: Class C65 variants do not receive BP4.
  • SpliceAI case result: maximum delta score 0.01, which is below the VCEP's no-predicted-splicing threshold of 0.2, but this does not overcome the Class C65 exclusion.
Still missing
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt; the flowchart provides general rules rather than a variant row.
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; that file covers single amino acid in-frame deletions, not this missense variant.
  • The p.D208A notation was not found in PP3-BP4-codes.xlsx.txt, although the exact c.623A>C/p.Asp208Ala row was found and assigns PP3_moderate rather than BP4.
Sources
cspec ↗vcep_pp3_bp4_codes ↗spliceai ↗

Not assessed · 9 · no assessment recorded

PS1 VCEPNot assessed: p.Asp208Ala has SpliceAI max delta 0.01, but no qualifying pathogenic or likely pathogenic same-amino-acid comparator was identified. Details ▾Hide ▴
Reasoning

The variant is a missense change, p.Asp208Ala, and SpliceAI reports a maximum delta score of 0.01, satisfying the VCEP's no-splicing-difference prerequisite. However, the available evidence does not identify a different nucleotide change producing the same amino-acid change, asserted as pathogenic or likely pathogenic under the TP53 VCEP specifications. ClinVar classifies the exact variant as uncertain significance, and the same-residue comparator collection contains zero usable candidates; therefore PS1 cannot be applied or excluded from a complete comparator search.

VCEP rule
This rule code can only be used to compare variants asserted as pathogenic or likely pathogenic following the ClinGen TP53 VCEP’s specifications. Must confirm there is no difference using RNA data or SpliceAI (SpliceAI < 0.2).
Evidence considered
  • The variant is NP_000537.3:p.(Asp208Ala), a missense change.
  • SpliceAI maximum delta score is 0.01, below the VCEP's <0.2 no-difference requirement.
  • ClinVar reports the exact variant as Uncertain significance with one single-submitter record.
  • The same-residue comparator search recorded zero same-residue candidates and no expert-panel or non-expert-majority pathogenic/likely pathogenic candidates; the search also reported an HTTP 429 retrieval error.
Still missing
  • A qualifying pathogenic or likely pathogenic TP53 variant producing the same amino-acid change, with VCEP-based classification, is required.
Sources
cspec ↗clinvar ↗spliceai ↗pm5_candidates
PS2 VCEPNot assessed: no documented de novo event, parental testing, or proband cancer points are available to reach the VCEP's 1-point PS2 Supporting threshold. Details ▾Hide ▴
Reasoning

No case-specific evidence documents a de novo occurrence of NM_000546.5:c.623A>C (p.Asp208Ala/p.D208A), confirmed parental testing, or an affected proband with the LFS-associated cancer point values needed to evaluate PS2. The governing CSPEC assigns PS2 Supporting at 1 point, Moderate at 2-3 points, Strong at 4-7 points, and Very Strong at >=8 points. The required VCEP Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found. Therefore PS2 cannot be assessed from the available evidence.

VCEP rule
≥ 8 points ... 4-7 points ... 2-3 points ... 1 point
Evidence considered
  • The case evidence bundle contains no documented proband, parental testing, de novo, meiosis, or family segregation result for this variant.
  • Searched Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found.
  • The TP53 VCEP CSPEC PS2 strength thresholds are Supporting = 1 point, Moderate = 2-3 points, Strong = 4-7 points, and Very Strong = >=8 points.
Still missing
  • No case-specific de novo status or parental testing result is documented for NM_000546.5:c.623A>C.
  • No proband phenotype and LFS-associated cancer point assignment is documented.
  • No entry for c.623A>C, p.Asp208Ala, or p.D208A was found when searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application ↗
PS4 VCEPNot assessed: no proband phenotype or PS4 point total is available to compare with the VCEP's 1-1.5, 2-3.5, 4-7.5, or >=8 thresholds. Details ▾Hide ▴
Reasoning

The TP53 VCEP assigns PS4 from proband points: 1-1.5 points for Supporting, 2-3.5 for Moderate, 4-7.5 for Strong, and at least 8 for Very Strong. The required case phenotype and proband point data are unavailable. The governing PS4-Points-Table.pdf was searched for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found, which does not establish absence of phenotype evidence.

VCEP rule
PS4 strength is assigned by total proband points.
Evidence considered
  • TP53 VCEP PS4 rule: Supporting requires 1-1.5 points, Moderate 2-3.5 points, Strong 4-7.5 points, and Very Strong >=8 points.
  • PS4-Points-Table.pdf was searched under c.623A>C, p.Asp208Ala, and p.D208A; no matching variant-specific row was found.
Still missing
  • No proband cancer phenotype or applicable Revised Chompret, Classic LFS, or HER2+ breast cancer point information is available.
  • PS4-Points-Table.pdf was searched for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found.
Sources
cspec ↗vcep_ps4_points_table ↗
PM1 VCEPNot assessed: D208 is outside the six listed hotspot codons, while the required same-amino-acid somatic count for the reported hotspot is unavailable. Details ▾Hide ▴
Reasoning

p.Asp208Ala is not within the VCEP-listed codons 175, 245, 248, 249, 273, or 282. The case records that D208 lies in a statistically significant cancer hotspot, but it does not provide the required number of somatic occurrences for the same amino-acid change; the hotspot source data are empty and marked as partially parsed. The TP53 vcep_materials.json domain_tables object is empty, so there is no authoritative domain-table entry to evaluate. Because the applicable hotspot threshold cannot be evaluated, PM1 is not assessed.

VCEP rule
There are several known major hotspots for the TP53 gene. This code can be used for variants within the following codons using canonical transcript NM\_000546.4: 175, 245, 248, 249, 273, 282 This code can also be used for germline missense variants seen in cancerhotspots.org (v2) with ≥ 10 somatic occurrences for the same amino acid change. This follows the recommendation from the ClinGen Germline/Somatic Variant Curation Subcommittee (PMID: 30311369). ... Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change.
Evidence considered
  • The VCEP lists codons 175, 245, 248, 249, 273, and 282 for the codon-based PM1 path; residue 208 is not listed.
  • The case's cancerhotspots result identifies TP53 D208 as a statistically significant hotspot, but source_data is empty and the record is marked partially parsed, so no same-amino-acid somatic occurrence count is available.
  • vcep_materials.json contains an empty domain_tables object for TP53; therefore no authoritative approved-domain entry is available for residue 208.
Still missing
  • The cancerhotspots.org v2 same-amino-acid somatic occurrence count for TP53 D208A is required to test the VCEP's 2-9 or ≥10 thresholds.
Sources
cspec ↗
PM5 VCEPNot assessed: residue 208 has zero usable same-residue comparator variants, so the VCEP pathogenicity and Grantham requirements cannot be tested. Details ▾Hide ▴
Reasoning

The variant is a missense change at residue 208, so PM5 is applicable in principle. The available comparator collection found zero same-residue candidates and no pathogenic or likely pathogenic comparator classified according to the TP53 VCEP; it also reported an HTTP 429 retrieval error. Without a qualifying comparator, the VCEP's pathogenicity-count and Grantham comparison requirements cannot be evaluated.

VCEP rule
This code can be applied for a missense change at an amino acid residue where one or more pathogenic/likely pathogenic variants have been identified. The other variant must be interpreted as pathogenic or likely pathogenic following the ClinGen TP53 VCEP’s specifications. The previously established pathogenic/likely pathogenic variant must reach a classification of pathogenicity without PM5. ... Grantham should be used to compare the variants. The variant being evaluated must be equal or worse (value is greater than) than the known pathogenic variant (i.e. the variant residue should be equally chemically different or more chemically different than the known pathogenic residue in comparison to the wild type residue). Splicing should be ruled out with either RNA data or SpliceAI (SpliceAI < 0.2).
Evidence considered
  • The variant is NP_000537.3:p.(Asp208Ala), a missense change at residue 208.
  • The PM5 comparator collection contains zero same-residue candidates, zero expert-panel pathogenic/likely pathogenic candidates, and zero non-expert-majority pathogenic/likely pathogenic candidates; it also reports an HTTP 429 retrieval error.
  • SpliceAI maximum delta score is 0.01, below the VCEP's <0.2 splicing threshold, but no qualifying comparator is available for the required Grantham comparison.
Still missing
  • A different missense variant at residue 208 classified as pathogenic or likely pathogenic under the TP53 VCEP, including its PM5-independent classification and Grantham comparison, is required.
Sources
cspec ↗pm5_candidatesspliceai ↗
PP1 VCEPNot assessed: no documented cosegregation meioses are available to meet the VCEP minimum of 3-4 meioses for PP1 Supporting. Details ▾Hide ▴
Reasoning

No case-specific affected-family-member genotypes, phenotype information, or cosegregation meioses are documented for NM_000546.5:c.623A>C (p.Asp208Ala/p.D208A). The TP53 VCEP requires cosegregation in 3-4 meioses for PP1 Supporting, 5-6 meioses for PP1 Moderate, or at least 7 meioses across more than 1 family for PP1 Strong. The required VCEP Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found. PP1 is therefore not assessed.

VCEP rule
Cosegregation must be observed in ≥ 7 meioses across > 1 family ... Cosegregation must be observed in 5-6 meioses in/across 1 or more families ... Cosegregation must be observed in 3-4 meioses in/across 1 or more families
Evidence considered
  • The case evidence bundle contains no affected-family-member genotypes, relationships, phenotype details, or cosegregation meiosis count for this variant.
  • Searched Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found.
  • The TP53 VCEP PP1 thresholds are Supporting for 3-4 meioses, Moderate for 5-6 meioses, and Strong for at least 7 meioses across more than 1 family.
Still missing
  • No affected relatives, tested genotypes, or family relationships are documented.
  • No cosegregation meiosis count is documented.
  • No entry for c.623A>C, p.Asp208Ala, or p.D208A was found when searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application ↗
PP4 VCEPNot assessed: VAF, multigene-panel detection, and required clinical exclusions are unavailable for comparison with the VCEP's PP4 rule. Details ▾Hide ▴
Reasoning

The TP53 VCEP PP4 rule is a low-VAF somatic-origin rule requiring observation of the variant with VAF 5-35% for Supporting, or at least 2 independent observations with VAF 5-25% for Moderate; it also requires detection on multigene panel testing and excludes blood cancer and BA1/BS1 cases. The available case evidence does not provide VAF, multigene-panel detection, or the required clinical exclusions.

VCEP rule
At least 2 independent observations of the variant with VAF 5-25%; Supporting: observation of the variant with VAF 5-35% (i.e., once or multiple times with VAF >25-35% and/or once with VAF 5-25%).
Evidence considered
  • The VCEP PP4 rule requires at least 2 independent observations with VAF 5-25% for Moderate or observation with VAF 5-35% for Supporting, with additional assay and clinical caveats.
  • The case evidence contains no usable VAF or multigene-panel observation for this variant.
Still missing
  • No VAF measurement or independent observation count is available.
  • No evidence confirms detection on multigene panel testing or evaluates the VCEP's blood-cancer, BA1, and BS1 exclusions.
Sources
cspec ↗
BS2 Not assessed: no qualifying single-source count of unrelated female carriers aged at least 60 years without cancer is available. Details ▾Hide ▴
Reasoning

The TP53 VCEP BS2 rule requires counts of unrelated females aged at least 60 years without cancer from a single source, with separate thresholds for supporting, moderate, and strong evidence. No qualifying individual-level carrier observations, ages, sex, cancer status, source provenance, or sarcoma exclusions are available for this variant.

Still missing
  • A single-source cohort with qualifying unrelated female carriers, ages, cancer status, and sarcoma exclusions is unavailable.
BS4 VCEPNot assessed: no affected relatives with documented absence of the variant are available to demonstrate the VCEP's BS4 lack-of-segregation rule. Details ▾Hide ▴
Reasoning

No case-specific affected family members with a documented negative genotype for NM_000546.5:c.623A>C (p.Asp208Ala/p.D208A) are provided. The TP53 VCEP BS4 rule requires lack of segregation in affected family members diagnosed with LFS-associated cancers as described in the VCEP cancer table. Because neither affected relatives nor their variant test results are documented, BS4 cannot be assessed. The required VCEP Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found.

VCEP rule
Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).
Evidence considered
  • The case evidence bundle contains no documented affected relatives, LFS-associated cancer diagnoses in relatives, or negative variant tests in affected family members.
  • Searched Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found.
Still missing
  • No affected family members with LFS-associated cancers are documented.
  • No variant test results for affected family members are documented.
  • No entry for c.623A>C, p.Asp208Ala, or p.D208A was found when searching Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.623A>C is a missense substitution at p.Asp208Ala, whereas the TP53 PVS1 rule covers null, splice-site, frameshift, nonsense, and copy-number variants. Details ▾Hide ▴
Reasoning

PVS1 is not applicable because NM_000546.5:c.623A>C (NP_000537.3:p.(Asp208Ala), p.(D208A)) is a missense substitution in exon 6, not a null, nonsense, frameshift, canonical splice-site, or copy-number variant named by the TP53 VCEP PVS1 rules. The PVS1-Flowchart.pdf and PVS1-Splicing-Worksheet.xlsx were searched for c.623A>C, p.Asp208Ala, and p.D208A; no variant-specific entry was found.

VCEP rule
Not Applicable
Evidence considered
  • Variant consequence and transcript mapping: NM_000546.5:c.623A>C is NP_000537.3:p.(Asp208Ala) / p.(D208A), a missense substitution in exon 6.
  • ClinGen TP53 VCEP PVS1 rule: the specified PVS1 paths cover initiation-codon, nonsense, frameshift, canonical splice-site, deletion, duplication, and other null-variant consequences; this missense substitution does not lie on one of those paths.
  • PVS1-Flowchart.pdf.txt searched for c.623A>C, p.Asp208Ala, and p.D208A: no variant-specific entry found.
  • PVS1-Splicing-Worksheet.xlsx.txt searched for c.623A>C, p.Asp208Ala, and p.D208A: no variant-specific entry found.
Still missing
  • No entry for c.623A>C, p.Asp208Ala, or p.D208A was found in PVS1-Flowchart.pdf.txt.
  • No entry for c.623A>C, p.Asp208Ala, or p.D208A was found in PVS1-Splicing-Worksheet.xlsx.txt.
Sources
cspec ↗vcep_pvs1_flowchart ↗vcep_pvs1_splicing_worksheet ↗
PM3 VCEPNot applicable: the TP53 VCEP explicitly states that PM3 does not apply to TP53/Li-Fraumeni syndrome. Details ▾Hide ▴
Reasoning

PM3 is not applicable under the TP53 VCEP specification because the VCEP explicitly excludes this criterion for TP53/Li-Fraumeni syndrome. No phase, affected-proband, or trans observations can change that criterion-level applicability determination.

VCEP rule
This rule does not apply to TP53/Li-Fraumeni syndrome.
Evidence considered
  • ClinGen TP53 VCEP specification v2.4: PM3 is marked not applicable and states, "This rule does not apply to TP53/Li-Fraumeni syndrome."
Sources
cspec ↗
PM4 VCEPNot applicable: the TP53 VCEP explicitly marks PM4 as Not Applicable for this specification. Details ▾Hide ▴
Reasoning

The TP53 VCEP CSPEC entry explicitly marks PM4 as Not Applicable. Therefore no PM4 assessment is made for this missense substitution, regardless of its unchanged protein length.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen TP53 VCEP Version 2.4 CSPEC entry for PM4: applicability is listed as Not Applicable.
Sources
cspec ↗
PM6 VCEPNot applicable: the TP53 VCEP explicitly marks PM6 as Not Applicable for this specification. Details ▾Hide ▴
Reasoning

The TP53 VCEP CSPEC explicitly marks PM6 as Not Applicable. No PM6 evidence is therefore evaluated or applied.

VCEP rule
Not Applicable
Evidence considered
  • The TP53 VCEP CSPEC entry for PM6 states: Not Applicable.
Sources
cspec ↗
PP2 VCEPNot applicable: the TP53 VCEP explicitly marks PP2 as not applicable. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks PP2 as not applicable for this framework, so the missense mechanism and benign-missense-rate concept are not used for this criterion.

VCEP rule
Not applicable
Evidence considered
  • The TP53 VCEP criterion entry lists PP2 applicability as Not applicable and its instructions as Not applicable.
Sources
cspec ↗
PP5 VCEPNot applicable: the TP53 VCEP explicitly prohibits use of PP5. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks PP5 as not applicable for this VCEP and does not permit its use.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The TP53 VCEP PP5 entry states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP1 VCEPNot applicable: the TP53 VCEP excludes BP1 because truncating variants account for only a portion of TP53 disease-causing variants. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks BP1 as not applicable because truncating variants account for only a portion of disease-causing variants; BP1 is therefore not applied to this missense variant.

VCEP rule
This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants.
Evidence considered
  • The TP53 VCEP criterion entry marks BP1 as Not applicable and states that truncating variants account for only a portion of disease-causing variants.
Sources
cspec ↗
BP2 VCEPNot applicable: the TP53 VCEP marks BP2 not applicable, regardless of the specified trans or phase-unknown observation scenarios. Details ▾Hide ▴
Reasoning

BP2 is marked not applicable by the TP53 VCEP specification. The specification describes trans-phase-confirmed observations or at least three phase-unknown observations involving at least two different pathogenic or likely pathogenic TP53 variants, but does not make BP2 applicable for this VCEP.

VCEP rule
Evidence code can be applied in either scenario: Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR when there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two differemt pathogenic or likely pathogenic TP53 variants.
Evidence considered
  • ClinGen TP53 VCEP specification v2.4: BP2 is marked not applicable; its listed scenarios are a phase-confirmed trans observation or at least three phase-unknown observations with at least two different pathogenic or likely pathogenic TP53 variants.
Sources
cspec ↗
BP3 VCEPNot applicable: the TP53 VCEP explicitly marks BP3 as Not Applicable for this specification. Details ▾Hide ▴
Reasoning

The TP53 VCEP CSPEC entry explicitly marks BP3 as Not Applicable. Therefore repeat-region or in-frame-deletion considerations do not produce a BP3 assessment for this missense substitution.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen TP53 VCEP Version 2.4 CSPEC entry for BP3: applicability is listed as Not Applicable.
Sources
cspec ↗
BP5 VCEPNot applicable: the TP53 VCEP marks BP5 as not applicable regardless of alternate molecular-basis evidence. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks BP5 as not applicable; therefore alternate molecular-basis evidence is not evaluated under this criterion.

VCEP rule
Not applicable
Evidence considered
  • The TP53 VCEP BP5 entry lists the criterion as not applicable and gives the instruction 'Not applicable.'
Sources
cspec ↗
BP6 VCEPNot applicable: the TP53 VCEP explicitly prohibits use of BP6. Details ▾Hide ▴
Reasoning

The TP53 VCEP marks BP6 as not applicable for this VCEP and does not permit its use.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The TP53 VCEP BP6 entry states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP7 N/ANot applicable: c.623A>C is an exonic missense variant, whereas BP7 applies only to synonymous or intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to synonymous (silent) or intronic variants. NM_000546.5:c.623A>C is an exonic missense variant producing p.Asp208Ala, so BP7 is outside its governing scope and is not evaluated from the available SpliceAI result.

VCEP rule
A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023 (PMID: 37352859).
Evidence considered
  • Variant normalization identifies NM_000546.5:c.623A>C as NP_000537.3:p.(Asp208Ala), a missense variant in exon 6.
  • The VCEP flowchart and CSPEC BP7 rule define the relevant BP7 paths for synonymous and intronic variants; neither path covers this exonic missense variant.
Still missing
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt; the flowchart provides general rules rather than a variant row.
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in PP3-BP4-codes.xlsx.txt under the p.D208A notation; the exact c.623A>C/p.Asp208Ala row is a missense PP3 assignment, not a BP7 entry.
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; that file covers single amino acid in-frame deletions, not this missense variant.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 ↗

Identifiers

Gene
TP53
Transcript
NM_000546.5
Coding (HGVS c.)
NM_000546.5:c.623A>C
Protein (HGVS p.)
NP_000537.3:p.(Asp208Ala)
GRCh38
chr17:7674908 T>G
GRCh37
chr17:7578226 T>G
Location and type
Exon 6 · missense
ClinVar
2759300
COSMIC
COSV106384816

Gene diagram

Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.

TP53NM_000546.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +46 bp
0.002
SpliceAI acceptor gainat -205 bp
0.000
SpliceAI donor lossat -54 bp
0.010
SpliceAI donor gainat -315 bp
0.000
Pangolin splice lossmagnitude shown
-0.014
Pangolin splice gain
0.004

Other predictors

REVEL
0.931
BayesDel
0.596

How the predictions were used

PP3 ModerateVCEPMet at moderate strength: the VCEP table pre-assigns PP3_moderate for c.623A>C with BayesDel 0.596355 (Class C65). Details ▾Hide ▴
Reasoning

The variant is a missense change, NM_000546.5:c.623A>C (p.Asp208Ala/p.D208A). The governing TP53 Supplementary Table S2 contains the exact row c.623A>C, p.Asp208Ala, Class C65, BayesDel 0.596355, and pre-assigns PP3_moderate. That VCEP pre-assignment is controlling. The case's SpliceAI maximum delta score is 0.01, below the VCEP's no-predicted-splicing threshold of 0.2, so there is no splice-effect conflict with the missense PP3 assignment.

VCEP rule
**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants)_ aGVGD Class C65 and BayesDel score ≥ 0.16
Evidence considered
  • PP3-BP4-codes.xlsx, Supplementary Table S2 exact row: c.623A>C | p.Asp208Ala | Class C65 | BayesDel 0.596355 | PP3_moderate | 0.01.
  • The VCEP table's exact pre-assigned PP3_moderate code is applied directly and outranks an independent recalculation.
  • SpliceAI case result: DS_AG 0.0, DS_AL 0.002, DS_DG 0.0, DS_DL 0.01; maximum delta score 0.01.
Still missing
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt; the flowchart provides general rules rather than a variant row.
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; that file covers single amino acid in-frame deletions, not this missense variant.
  • The p.D208A notation was not found in PP3-BP4-codes.xlsx.txt, although the exact c.623A>C/p.Asp208Ala row was found.
Sources
cspec ↗vcep_pp3_bp4_codes ↗spliceai ↗
BP4 VCEPNot met: BP4 is explicitly barred for the VCEP Class C65 row, despite BayesDel 0.596355 and SpliceAI maximum delta 0.01. Details ▾Hide ▴
Reasoning

The variant is a missense change and the VCEP provides a missense BP4 path requiring BayesDel below 0.16 and no predicted splicing impact, but explicitly excludes Class C65 variants from BP4. The exact VCEP table row classifies c.623A>C as Class C65 with BayesDel 0.596355 and assigns PP3_moderate, so BP4 cannot be applied despite the SpliceAI maximum delta of 0.01 being below 0.2.

VCEP rule
**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants):_ BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI < 0.2)
Evidence considered
  • PP3-BP4-codes.xlsx, Supplementary Table S2 exact row: c.623A>C | p.Asp208Ala | Class C65 | BayesDel 0.596355 | PP3_moderate | 0.01; no BP4 code is assigned.
  • The VCEP missense BP4 rule's Class C65 exception applies directly: Class C65 variants do not receive BP4.
  • SpliceAI case result: maximum delta score 0.01, which is below the VCEP's no-predicted-splicing threshold of 0.2, but this does not overcome the Class C65 exclusion.
Still missing
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt; the flowchart provides general rules rather than a variant row.
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; that file covers single amino acid in-frame deletions, not this missense variant.
  • The p.D208A notation was not found in PP3-BP4-codes.xlsx.txt, although the exact c.623A>C/p.Asp208Ala row was found and assigns PP3_moderate rather than BP4.
Sources
cspec ↗vcep_pp3_bp4_codes ↗spliceai ↗
BP7 N/ANot applicable: c.623A>C is an exonic missense variant, whereas BP7 applies only to synonymous or intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to synonymous (silent) or intronic variants. NM_000546.5:c.623A>C is an exonic missense variant producing p.Asp208Ala, so BP7 is outside its governing scope and is not evaluated from the available SpliceAI result.

VCEP rule
A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023 (PMID: 37352859).
Evidence considered
  • Variant normalization identifies NM_000546.5:c.623A>C as NP_000537.3:p.(Asp208Ala), a missense variant in exon 6.
  • The VCEP flowchart and CSPEC BP7 rule define the relevant BP7 paths for synonymous and intronic variants; neither path covers this exonic missense variant.
Still missing
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt; the flowchart provides general rules rather than a variant row.
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in PP3-BP4-codes.xlsx.txt under the p.D208A notation; the exact c.623A>C/p.Asp208Ala row is a missense PP3 assignment, not a BP7 entry.
  • No c.623A>C, p.Asp208Ala, or p.D208A entry was found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; that file covers single amino acid in-frame deletions, not this missense variant.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.931. BayesDel score = 0.596355.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Rescuing the function of mutant p53.
    No paper-specific finding is recorded.
    PMID 11900253 ↗
  • Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigen
    No paper-specific finding is recorded.
    PMID 8023157 ↗
  • Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
    Kato S et al. · 2003
    The paper reports a comprehensive yeast-based transactivation analysis of 2,314 TP53 missense mutants, but it does not explicitly mention TP53 c.623A>C or p.(D208A). The variant-specific Kato result used here is the VCEP Functional-worksheet.xlsx row, not an individually reported result in the paper extract.
    Does not name this variant
    PMID 12826609 ↗
    Quoted passage
    Approximately two-thirds (64.0%) of the mutants in the core domain of p53 were inactive

    Results, “Evaluation of 2,314 Missense Mutations on Sequence-Specific Trans-activation”

  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    Saslow D et al. · 2007
    No paper-specific finding is recorded.
    PMID 17392385 ↗
  • Li-Fraumeni Syndrome.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301488 ↗
  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    Lu KH et al. · 2014
    No paper-specific finding is recorded.
    PMID 24493721 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    No paper-specific finding is recorded.
    PMID 26389210 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    No paper-specific finding is recorded.
    PMID 26389258 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2759300)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.931. BayesDel score = 0.596355.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV106384816, n = 1 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.