Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
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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.
Met at very strong strength: p.Tyr103Ter is a nonsense variant upstream of TP53 p.Lys351, satisfying the VCEP NMD PVS1 rule.
PM2Supporting
PM2 · supporting
Met at supporting: the variant is absent from all reported gnomAD datasets, consistent with an allele frequency below the TP53 VCEP PM2 threshold of 0.00003.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Likely Pathogenic: PVS1 very strong (8 points) plus PM2 supporting (1 point) total 9 points under the TP53 VCEP 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 2 not met · 6 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is met at very strong strength under the TP53-specific VCEP flowchart because p.Tyr103Ter is a nonsense variant upstream of p.Lys351 and is predicted to undergo NMD.
PM4 and BP3 are not applicable under the TP53 VCEP specification.
For this nonsense TP53 variant, the governing Version 2.4 VCEP framework applies PS2 to confirmed de novo evidence, excludes PM6, requires explicit carrier-and-phenotype meioses for PP1, and requires demonstrated non-segregation for BS4.
The exact variant is reported in one LFS-like family, but the available evidence does not establish parental testing, variant-positive affected relatives, countable cosegregation, or affected non-carriers; therefore PS2, PP1, and BS4 remain not assessed and PM6 is not applicable.
For this nonsense TP53 variant, the governing VCEP supports only a PS4 assessment from explicitly documented phenotype points; the available case report does not provide a sufficiently explicit proband-level PS4 point total.
PP4, PP5, BP5, and BP6 are not assigned because the VCEP-specific requirements are absent or explicitly prohibit those criteria.
All three requested criteria are not_applicable because the variant is a nonsense/truncating change; no computational predictor score can change that upstream scope determination.
Population evidence is driven by the TP53 VCEP Version 2.4 thresholds: absence from the available gnomAD datasets supports PM2_Supporting, while no benign-frequency or qualifying healthy-carrier evidence supports BA1, BS1, or BS2.
No criteria match.
Met · 2
PVS1Very strongMet at very strong strength: p.Tyr103Ter is a nonsense variant upstream of TP53 p.Lys351, satisfying the VCEP NMD PVS1 rule.
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Reasoning
NM_000546.5:c.309C>A is a nonsense variant producing NP_000537.3:p.(Tyr103Ter)/p.(Y103*). Variant Validator places it in exon 4 of the TP53 transcript, and the case normalization predicts termination at amino acid 103 instead of the normal stop at amino acid 394. TP53 loss of function is an established disease mechanism under the TP53 VCEP framework. The governing TP53 PVS1 flowchart states that nonsense variants upstream of p.Lys351 are predicted to undergo nonsense-mediated decay and receive full PVS1. Codon 103 is upstream of p.Lys351, is not in exon 11 or the 3'-most 50 nucleotides of exon 10, and therefore does not trigger a VCEP downgrade. The exact variant was not listed in PVS1-Flowchart.pdf or PVS1-Splicing-Worksheet.xlsx; the flowchart's general nonsense-variant rule governs this non-splice nonsense variant. The exact variant was also reported as nonsense p.Y103X and predicted to result in protein truncation in a germline TP53 family study.
Rule
TP53 VCEP PVS1 flowchart: nonsense upstream of p.Lys351, predicted to undergo NMD, receives full PVS1.
Evidence considered
The TP53 VCEP CSPEC version 2.4 identifies PVS1 as applicable to nonsense variants and directs use of the TP53 PVS1 decision tree.
PVS1-Flowchart.pdf states that a nonsense variant upstream of p.Lys351 is predicted to undergo NMD and receives PVS1.
The case normalization gives NM_000546.5:c.309C>A as NP_000537.3:p.(Tyr103Ter)/p.(Y103*) and predicts the protein terminates at residue 103 rather than the normal residue 394.
Variant Validator places c.309C>A in exon 4; this is outside the TP53 VCEP exceptions for exon 11 and the 3'-most 50 nucleotides of exon 10.
PMID:17224268 reports the exact germline TP53 nonsense change p.Y103X and states that it is predicted to result in protein truncation.
Still missing
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry was found in PVS1-Flowchart.pdf.txt; the general flowchart rule was applied.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry was found in PVS1-Splicing-Worksheet.xlsx.txt; this is a non-canonical-splice nonsense variant, so the worksheet is not the applicable assignment table.
PM2SupportingMet at supporting: the variant is absent from all reported gnomAD datasets, consistent with an allele frequency below the TP53 VCEP PM2 threshold of 0.00003.
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Reasoning
The ClinGen TP53 VCEP Version 2.4 applies PM2 only at Supporting strength when the variant allele frequency is less than 0.00003 in gnomAD or another large sequenced population; if multiple alleles occur in an ancestry group, that group's frequency must remain below 0.00004. NM_000546.5:c.309C>A (p.Tyr103Ter) is absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer, supporting an allele frequency below the VCEP threshold in the available population datasets.
Rule
TP53 VCEP Version 2.4 PM2: allele frequency <0.00003 in gnomAD or another large sequenced population; if multiple alleles are present in an ancestry group, that group's frequency must be <0.00004; apply at Supporting strength.
Evidence considered
The TP53 VCEP Version 2.4 specifies PM2 only at Supporting strength for allele frequency <0.00003, with <0.00004 required for any ancestry group containing multiple variant alleles; founder-effect groups are ignored.
The variant was absent from gnomAD v2.1 and gnomAD v4.1.
The variant was also absent from the reported gnomAD v2.1 non-cancer exome subset and gnomAD v3.1 non-cancer genome subset; no alternative frequency or homozygote signal was reported.
BA1Not met: the variant is absent from gnomAD v2.1 and v4.1, with no ancestry-specific FAF meeting the TP53 VCEP BA1 threshold of 0.001.
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Reasoning
The ClinGen TP53 VCEP Version 2.4 requires a filtering allele frequency (FAF) of at least 0.001 in a single eligible continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles, for BA1. NM_000546.5:c.309C>A (p.Tyr103Ter) is absent from gnomAD v2.1 and gnomAD v4.1, so no qualifying population frequency or allele count reaches the VCEP BA1 threshold.
Rule
TP53 VCEP Version 2.4 BA1: FAF >=0.001 in a single eligible continental subpopulation, with >=2,000 alleles tested and >=2 alleles present; founder-effect groups are excluded.
Evidence considered
The TP53 VCEP Version 2.4 specifies BA1 at filtering allele frequency (FAF) >=0.001 in one eligible continental ancestry group, requiring at least 2,000 alleles tested and at least 2 variant alleles.
The variant was absent from gnomAD v2.1 and gnomAD v4.1; therefore, no qualifying FAF at or above 0.001 was observed.
BS1Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than showing the TP53 VCEP BS1 FAF interval of 0.0003 to below 0.001.
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Reasoning
The ClinGen TP53 VCEP Version 2.4 requires a filtering allele frequency of at least 0.0003 but less than 0.001 in one eligible continental ancestry group, with at least 2,000 alleles tested and at least 2 variant alleles, for BS1. NM_000546.5:c.309C>A (p.Tyr103Ter) is absent from gnomAD v2.1 and gnomAD v4.1, so the required frequency interval is not met.
Rule
TP53 VCEP Version 2.4 BS1: FAF >=0.0003 and <0.001 in a single eligible continental subpopulation, with >=2,000 alleles tested and >=2 alleles present; founder-effect groups are excluded.
Evidence considered
The TP53 VCEP Version 2.4 specifies BS1 at FAF >=0.0003 and <0.001 in one eligible continental subpopulation, requiring at least 2,000 alleles tested and at least 2 variant alleles.
The variant was absent from gnomAD v2.1 and gnomAD v4.1; no population frequency in the VCEP BS1 interval was observed.
PS2Not assessed: the exact variant was reported in one LFS-like family, but confirmed parental testing and de novo status required for PS2 are not documented.
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Reasoning
The TP53 VCEP specifies PS2 exclusively for confirmed de novo evidence, with points assigned according to the proband cancer and confirmed versus assumed maternity and paternity. The exact variant was reported as Y103X in family 2 of Manoukian et al. (PMID:17224268), whose family history included breast cancer at 31, osteosarcoma at 17, and stomach cancer at 60-70, but the available report does not establish parental testing, maternity, paternity, or a de novo origin. Therefore no PS2 points can be assigned. The governing VCEP table was searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no variant-specific pre-assigned entry was found.
Rule
TP53 VCEP PS2: de novo points are tallied using the LFS cancer table according to confirmed or assumed maternity and paternity; Supporting = 1 point, Moderate = 2-3, Strong = 4-7, Very Strong >= 8.
Evidence considered
The TP53 VCEP Version 2.4 states that PS2 is used exclusively for de novo evidence and that PS2 points require tallying the proband cancer category with confirmed or assumed maternity and paternity.
The governing LFS cancer table assigns 4 points for a strongly associated cancer when maternity and paternity are confirmed, 2 points when they are assumed, and PS2 strength thresholds of Supporting 1, Moderate 2-3, Strong 4-7, and Very Strong at least 8 points.
Manoukian et al. explicitly reports the exact nonsense alteration as Y103X in family 2 and describes a Li-Fraumeni-like family with breast cancer at age 31, osteosarcoma at age 17, and stomach cancer at age 60-70, but does not document parental testing or de novo status.
The exact variant was searched under c.309C>A, p.Tyr103Ter, and p.Y103* in the governing VCEP full-text table; no variant-specific pre-assigned entry was found.
Still missing
No parental testing or confirmed maternity and paternity is documented for the exact variant in PMID:17224268.
No variant-specific entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/TP53/fulltext/Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt.
The proband cancer category and age are not sufficient to assign PS2 points without confirmed de novo status.
PS4Not assessed: one family reports p.Y103X, but the VCEP PS4 point total for the proband is not explicitly established.
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Reasoning
The TP53 VCEP governs PS4 with point-based phenotype rules: Revised Chompret criteria contribute 0.5 point, Classic LFS criteria contribute 1 point, HER2-positive breast cancer diagnosed below age 40 contributes 0.5 point, and the strength thresholds are Supporting 1-1.5, Moderate 2-3.5, Strong 4-7.5, and Very Strong >=8 points. The exact variant is reported in PMID:17224268 in Family 2, described as Li-Fraumeni-like, with breast cancer at age 31, osteosarcoma at age 17, and stomach cancer at age 60-70, but the available evidence does not explicitly establish which VCEP PS4 phenotype rule applies to the proband or provide a total point assignment. A direct search of the governing PS4-Points-Table.pdf for c.309C>A, p.Tyr103Ter, and p.Y103* found no exact-variant pre-assigned row. PS4 therefore cannot be assigned without human confirmation of the proband-level phenotype and applicable point total.
Rule
TP53 VCEP PS4: Revised Chompret = 0.5 point; Classic LFS = 1 point; HER2-positive breast cancer below age 40 = 0.5 point; Supporting = 1-1.5 points, Moderate = 2-3.5 points, Strong = 4-7.5 points, Very Strong >=8 points.
Evidence considered
The TP53 VCEP PS4 specification assigns 0.5 point for Revised Chompret criteria, 1 point for Classic LFS criteria, and 0.5 point for HER2-positive breast cancer below age 40; PS4 strength thresholds are Supporting 1-1.5, Moderate 2-3.5, Strong 4-7.5, and Very Strong >=8 points.
PMID:17224268 explicitly reports the exact TP53 nonsense variant as Y103X in Family 2, a Li-Fraumeni-like family with breast cancer at age 31, osteosarcoma at age 17, and stomach cancer at age 60-70.
Still missing
PS4-Points-Table.pdf was searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact-variant pre-assigned row was found.
The available report does not explicitly identify the applicable VCEP PS4 phenotype category or a total point assignment for the proband.
PP1Not assessed: one family report documents the variant and cancer history, but no variant-positive affected relatives or countable cosegregating meioses are provided.
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Reasoning
The TP53 VCEP requires PP1 meioses to be counted only for individuals who both carry the variant and have a relevant LFS-associated cancer, including through unaffected obligate carriers, with Supporting requiring 3-4 cosegregating meioses, Moderate 5-6, and Strong at least 7 across more than one family. PMID:17224268 reports the exact variant in family 2 and lists affected relatives or family-history cancers, but it does not provide genotype results for affected relatives, demonstrable cosegregation, or countable meioses. The governing VCEP table was searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no variant-specific pre-assigned entry was found.
Rule
TP53 VCEP PP1: count cosegregation only for variant carriers with relevant LFS-associated cancer, with Supporting = 3-4 meioses, Moderate = 5-6, and Strong >= 7 meioses across more than one family.
Evidence considered
The TP53 VCEP requires PP1 meioses to involve individuals who both carry the variant and have a relevant LFS-associated cancer; it permits counting through unaffected obligate carriers and assigns Supporting at 3-4, Moderate at 5-6, and Strong at least 7 cosegregating meioses.
Manoukian et al. reports Y103X in family 2 and describes breast cancer at age 31, osteosarcoma at age 17, and stomach cancer at age 60-70, but the extracted exact-variant report does not identify variant-positive affected relatives or provide segregation data.
The exact variant was searched under c.309C>A, p.Tyr103Ter, and p.Y103* in the governing VCEP full-text table; no variant-specific pre-assigned entry was found.
Still missing
PMID:17224268 does not document which affected family members carried the exact variant or provide a segregation pedigree sufficient to count meioses.
No countable cosegregating meioses are established, so no PP1 strength threshold is reached.
No variant-specific entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/TP53/fulltext/Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt.
PP4Not assessed: the VCEP PP4 VAF rule requires blood multigene-panel evidence, but no VAF or testing-context data are available.
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Reasoning
The TP53 VCEP PP4 rule is applicable only to a TP53 variant detected on multigene panel testing in blood at low variant allele fraction, with Supporting evidence for an observation at VAF 5-35% or Moderate evidence for at least two independent observations at VAF 5-25%; confirmed constitutional mosaicism is excluded and phenotype-based codes cannot be combined in the same individual. The case materials provide no VAF, multigene-panel, blood, or constitutional-mosaicism evidence for this variant. PP4 is therefore not assessed.
Rule
TP53 VCEP PP4: Supporting requires observation on multigene panel testing at VAF 5-35%; Moderate requires at least two independent observations at VAF 5-25%; do not apply for confirmed constitutional mosaicism or when phenotype-based codes are applied in the same individual.
Evidence considered
The TP53 VCEP PP4 rule requires a multigene-panel finding in blood at VAF 5-35% for Supporting or at least two independent observations at VAF 5-25% for Moderate, and excludes confirmed constitutional mosaicism.
Still missing
No VAF or blood multigene-panel testing context is available for applying the TP53 VCEP PP4 rule.
BS2Not assessed: no qualifying unrelated female carriers aged 60 or older without cancer were reported for comparison with the TP53 VCEP BS2 thresholds.
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Reasoning
The ClinGen TP53 VCEP Version 2.4 requires observations in at least 2 unrelated females aged at least 60 years without cancer for BS2_Supporting, 4-7 such individuals for BS2_Moderate, or at least 8 for BS2_Strong; all must come from one source, and females with sarcoma diagnosed at age 61 years or older are excluded. The available case evidence contains no qualifying carrier-level age, sex, cancer-status, source, or homozygote observations.
Rule
TP53 VCEP Version 2.4 BS2: >=2 unrelated females aged >=60 years without cancer from one source; 2-3 supporting, 4-7 moderate, and >=8 strong; exclude individuals with sarcoma diagnosed at age >=61 years.
Evidence considered
The TP53 VCEP Version 2.4 defines BS2_Supporting as 2-3 unrelated females aged at least 60 years without cancer from one source, BS2_Moderate as 4-7, and BS2_Strong as at least 8.
gnomAD v2.1 and v4.1 report the variant as absent and provide no qualifying carrier-level sex, age, cancer-status, source, or homozygote observations.
Still missing
A single-source dataset reporting at least 2 unrelated female TP53 variant carriers aged >=60 years without cancer is unavailable.
Carrier-level sex, age, cancer-status, source, and homozygote data are unavailable.
BS4Not assessed: no tested affected family member is documented as lacking the exact TP53 variant, so non-segregation cannot be demonstrated.
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Reasoning
The TP53 VCEP defines BS4 as strong evidence for lack of segregation in affected family members diagnosed with LFS-associated cancers, while cautioning that phenocopies and more than one pathogenic variant can confound apparent non-segregation. The available exact-variant report describes family cancer history but does not provide affected relatives who were tested negative for the variant or any other demonstrated non-segregation. Therefore BS4 cannot be applied.
Rule
TP53 VCEP BS4: strong evidence requires lack of segregation in affected family members with LFS-associated cancers; phenocopies and multiple pathogenic variants must be considered.
Evidence considered
The TP53 VCEP defines BS4 as lack of segregation in affected family members diagnosed with LFS-associated cancers listed in the governing LFS cancer table and cautions about phenocopies and multiple pathogenic variants.
The exact-variant report in PMID:17224268 documents family cancer history but does not report affected relatives who tested negative for the variant or otherwise demonstrate non-segregation.
The exact variant was searched under c.309C>A, p.Tyr103Ter, and p.Y103* in the governing VCEP full-text table; no variant-specific pre-assigned entry was found.
Still missing
No affected family member with a documented negative test for c.309C>A/p.Y103* is reported in the available evidence.
No variant-specific entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/TP53/fulltext/Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf.txt, the governing table referenced by the BS4 rule.
Not applicable · 18· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: c.309C>A is a nonsense change producing p.Tyr103Ter, not an amino-acid substitution eligible for same-amino-acid PS1.
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Reasoning
The TP53 VCEP specifies PS1 for variants with the same amino-acid change as a pathogenic variant, but NM_000546.5:c.309C>A is a nonsense variant producing p.Tyr103Ter rather than an amino-acid substitution; therefore PS1 is not applicable.
Rule
The TP53 VCEP permits PS1 for variants with the same amino-acid change as a pathogenic or likely pathogenic variant under the TP53 specifications.
Evidence considered
The TP53 VCEP PS1 rule applies to variants asserted as pathogenic or likely pathogenic under its specifications, within the same-amino-acid-change framework; this variant is p.Tyr103Ter, a nonsense consequence.
PS3N/ANot applicable: TP53 VCEP functional rules cover missense variants and small in-frame deletions, whereas this variant is a nonsense p.(Tyr103Ter).
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Reasoning
The ClinGen TP53 Expert Panel Specifications, version 2.4, define PS3 for functional assessment of TP53 missense variants and small in-frame deletions. This case is the nonsense variant NM_000546.5:c.309C>A, p.(Tyr103Ter)/p.(Y103*), so the missense/deletion functional-code rules do not apply. The governing Functional-worksheet.xlsx was searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact variant row was found. The functional flowchart likewise provides category-level instructions rather than an applicable nonsense-variant assignment. Gene-level or truncating-variant observations cannot be substituted for an applicable PS3 assignment under this VCEP rule.
Rule
PS3 is not applicable because the TP53 VCEP functional specification covers missense variants and small in-frame deletions, not nonsense variants.
Evidence considered
The ClinGen TP53 Expert Panel Specifications version 2.4 define PS3 functional rules for non-functional or partially functional missense variants and small in-frame deletions, with no applicable nonsense-variant rule.
The TP53 functional flowchart states that its PS3/BS3 protein-function application covers missense variants and small deletions.
The full Functional-worksheet.xlsx text was searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact row was found.
Case normalization identifies NM_000546.5:c.309C>A as the nonsense variant NP_000537.3:p.(Tyr103Ter), also represented as p.(Y103*).
Still missing
Functional-worksheet.xlsx: no exact entry was found for c.309C>A, p.Tyr103Ter, or p.Y103*.
Flowchart-for-application-of-functional-rule-codes.pdf: no variant-specific assignment was found; its instructions cover missense variants and small in-frame deletions, not nonsense variants.
PM1N/ANot applicable: p.Tyr103Ter is nonsense at codon 103, outside the VCEP PM1 missense codons 175, 245, 248, 249, 273, and 282.
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Reasoning
The governing TP53 VCEP PM1 rule applies to missense variants in codons 175, 245, 248, 249, 273, or 282, or to germline missense variants at cancer-hotspot residues meeting the specified occurrence thresholds. This variant is a nonsense change at codon 103, and vcep_materials.json contains no domain_tables entry for TP53; PM1 is therefore not applicable.
Rule
Missense variants in TP53 codons 175, 245, 248, 249, 273, or 282 qualify for PM1_Moderate; missense variants with 2-9 same-amino-acid cancer-hotspot occurrences qualify for PM1_Supporting and those with at least 10 qualify for PM1_Moderate.
Evidence considered
The TP53 VCEP PM1 rule lists missense codons 175, 245, 248, 249, 273, and 282, with an alternative cancer-hotspot rule also limited to missense variants.
PM3VCEPNot applicable: TP53 VCEP version 2.4 explicitly designates PM3 as not applicable.
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Reasoning
The ClinGen TP53 Expert Panel Specifications, version 2.4, explicitly designate PM3 as not applicable. TP53-related Li-Fraumeni syndrome is governed here as an autosomal-dominant disorder, so recessive allelic evidence based on affected individuals with pathogenic variants in trans is not used for this gene-specific framework. No phase, trans/cis, or affected-proband observation can override the governing VCEP designation.
VCEP rule
PM3 is not applicable under the ClinGen TP53 Expert Panel Specifications version 2.4.
Evidence considered
The ClinGen TP53 Expert Panel Specifications version 2.4 list PM3 as not applicable.
The governing TP53 framework specifies autosomal-dominant inheritance for Li-Fraumeni syndrome, making recessive in-trans affected-proband evidence inapplicable to this criterion.
PM4VCEPNot applicable: the TP53 VCEP explicitly excludes PM4, and this variant is a nonsense loss-of-function change rather than an in-frame length-altering variant.
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Reasoning
The TP53 VCEP CSPEC explicitly marks PM4 as Not Applicable. This variant is a nonsense loss-of-function variant, not an in-frame deletion or insertion causing a protein-length change to be evaluated under PM4; its consequence is addressed by the VCEP PVS1 framework instead.
VCEP rule
TP53 VCEP CSPEC PM4 applicability: Not Applicable.
Evidence considered
The TP53 VCEP CSPEC version 2.4 lists PM4 as Not Applicable.
The normalized consequence is nonsense, producing p.(Tyr103Ter), not an in-frame insertion or deletion.
PM5N/ANot applicable: p.Tyr103Ter is a nonsense variant, whereas the TP53 VCEP PM5 rule requires a missense variant at the same residue.
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Reasoning
The governing TP53 VCEP PM5 rule requires a missense variant at an amino-acid residue where different missense variants have previously been classified as pathogenic or likely pathogenic under the TP53 specifications. NM_000546.5:c.309C>A is a nonsense variant producing p.Tyr103Ter, so PM5 is not applicable.
Rule
PM5_Strong requires at least two different pathogenic missense variants at the residue; PM5_Moderate requires one different pathogenic missense variant; PM5_Supporting requires one different likely pathogenic missense variant with clinical pathogenicity data.
Evidence considered
The TP53 VCEP PM5 rule is restricted to missense variants compared with previously classified pathogenic or likely pathogenic missense variants at the same amino-acid residue; the collected PM5 assessment identifies the consequence as nonsense and no eligible comparator search applies.
PM6VCEPNot applicable: the TP53 VCEP explicitly dropped PM6 and requires all de novo evidence to be evaluated through PS2.
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Reasoning
The TP53 VCEP explicitly states that PM6 is not applicable because the VCEP has dropped PM6 and uses PS2 exclusively for de novo evidence. The PM6 rule entry directs reviewers to the combined PS2/de novo rule, so PM6 must not be assigned independently even though parental testing is not documented.
VCEP rule
TP53 VCEP PM6: Not applicable; the VCEP dropped PM6 and uses PS2 exclusively for de novo evidence.
Evidence considered
The TP53 VCEP Version 2.4 states that PM6 is not applicable and that, to avoid redundancy, PM6 was dropped in favor of PS2 exclusively for de novo evidence.
The TP53 VCEP PM6 entry directs reviewers to the combined PS2 rule rather than providing an independent PM6 application pathway.
PP2VCEPNot applicable: the governing TP53 VCEP explicitly designates PP2 as not applicable.
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Reasoning
The TP53 VCEP explicitly marks PP2 as not applicable. No generic fallback is permitted because an applicable gene-specific specification governs this case.
Evidence considered
The governing TP53 VCEP specification explicitly designates PP2 as not applicable.
PP3N/ANot applicable: p.(Y103*) is a nonsense variant, outside TP53 VCEP PP3 scope for missense, splice-region, intronic, or synonymous variants.
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Reasoning
Not applicable: NM_000546.5:c.309C>A is a nonsense variant, NP_000537.3:p.(Tyr103Ter)/p.(Y103*), not a missense, intronic, splice-region, or synonymous variant. The TP53 VCEP PP3 specification covers missense variants, single-amino-acid in-frame deletions, and exonic or intronic splice variants, but not truncating nonsense variants; therefore SpliceAI 0.098 and BayesDel 0.66 were not evaluated for PP3. No exact entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt or PP3-BP4-codes.xlsx.txt. The single-amino-acid deletion table contains the different variant p.Tyr103del, not this nonsense variant.
Rule
TP53 VCEP PP3 is not applicable to a nonsense/truncating variant.
Evidence considered
The case normalization identifies NM_000546.5:c.309C>A as NP_000537.3:p.(Tyr103Ter)/p.(Y103*), with consequence class nonsense.
The TP53 VCEP Version 2.4 PP3 rule applies to missense variants, single-amino-acid in-frame deletions, and exonic or intronic splice variants; it does not apply to nonsense variants.
The governing VCEP files were searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact target entry was found in the PP3/BP4 flowchart or lookup table, while the deletion table lists the different p.Tyr103del variant.
Still missing
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in PP3-BP4-codes.xlsx.txt.
No exact target entry found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; it contains the distinct p.Tyr103del variant.
PP5VCEPNot applicable: the TP53 VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel classification.
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Reasoning
The TP53 VCEP explicitly marks PP5 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact ClinVar record is classified Pathogenic by three clinical laboratories, but the record has zero expert-panel submissions and therefore does not meet the required exact-variant ClinVar expert-panel condition for PP5.
VCEP rule
TP53 VCEP PP5 is not applicable; an exact-variant ClinVar expert-panel Pathogenic or Likely Pathogenic classification would otherwise be required by the requested adjudication policy.
Evidence considered
The TP53 VCEP PP5 specification states: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The exact ClinVar record is Pathogenic from three clinical laboratories with review status criteria provided and zero expert-panel submissions; ordinary laboratory submissions do not trigger PP5.
BS3N/ANot applicable: TP53 VCEP benign functional rules cover missense variants and small in-frame deletions, whereas this variant is a nonsense p.(Tyr103Ter).
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Reasoning
The ClinGen TP53 Expert Panel Specifications, version 2.4, define BS3 for functional or partially functional TP53 missense variants and small in-frame deletions based on specified assay results. This case is the nonsense variant NM_000546.5:c.309C>A, p.(Tyr103Ter)/p.(Y103*), so the missense/deletion functional-code rules do not apply. The governing Functional-worksheet.xlsx was searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact variant row was found. The functional flowchart likewise provides category-level instructions rather than an applicable nonsense-variant assignment. Absence of an exact worksheet row and gene-level assay observations cannot establish BS3 for this truncating variant under the VCEP framework.
Rule
BS3 is not applicable because the TP53 VCEP functional specification covers missense variants and small in-frame deletions, not nonsense variants.
Evidence considered
The ClinGen TP53 Expert Panel Specifications version 2.4 define BS3 for functional or partially functional missense variants and small in-frame deletions, with no applicable nonsense-variant rule.
The TP53 functional flowchart states that its PS3/BS3 protein-function application covers missense variants and small deletions.
The full Functional-worksheet.xlsx text was searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact row was found.
Case normalization identifies NM_000546.5:c.309C>A as the nonsense variant NP_000537.3:p.(Tyr103Ter), also represented as p.(Y103*).
Still missing
Functional-worksheet.xlsx: no exact entry was found for c.309C>A, p.Tyr103Ter, or p.Y103*.
Flowchart-for-application-of-functional-rule-codes.pdf: no variant-specific assignment was found; its instructions cover missense variants and small in-frame deletions, not nonsense variants.
BP1VCEPNot applicable: the governing TP53 VCEP explicitly designates BP1 as not applicable.
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Reasoning
The TP53 VCEP explicitly marks BP1 as not applicable. No generic fallback is permitted because an applicable gene-specific specification governs this case.
Evidence considered
The governing TP53 VCEP specification explicitly designates BP1 as not applicable.
BP2VCEPNot applicable: TP53 VCEP version 2.4 explicitly designates BP2 as not applicable.
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Reasoning
The ClinGen TP53 Expert Panel Specifications, version 2.4, explicitly designate BP2 as not applicable. The TP53 gene-specific framework therefore does not use observations of the assessed variant in cis with a pathogenic variant, or in trans with a pathogenic variant in an unaffected individual, as BP2 evidence. No phase or inheritance observation can override the governing VCEP designation.
VCEP rule
BP2 is not applicable under the ClinGen TP53 Expert Panel Specifications version 2.4.
Evidence considered
The ClinGen TP53 Expert Panel Specifications version 2.4 list BP2 as not applicable.
The governing TP53 framework does not permit cis/trans allelic observations to be applied as BP2.
BP3VCEPNot applicable: the TP53 VCEP explicitly excludes BP3, and p.Tyr103Ter is a truncating nonsense variant rather than a benign repeat-region in-frame change.
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Reasoning
The TP53 VCEP CSPEC explicitly marks BP3 as Not Applicable. The variant is a nonsense change predicted to truncate TP53 and is not a benign in-frame change in a repetitive region, so BP3 cannot be applied.
VCEP rule
TP53 VCEP CSPEC BP3 applicability: Not Applicable.
Evidence considered
The TP53 VCEP CSPEC version 2.4 lists BP3 as Not Applicable.
The case consequence is nonsense p.(Tyr103Ter), with a predicted protein stop at residue 103 rather than the normal stop at residue 394.
BP4N/ANot applicable: p.(Y103*) is a nonsense variant, outside TP53 VCEP BP4 scope for missense, splice-region, intronic, or synonymous variants.
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Reasoning
Not applicable: NM_000546.5:c.309C>A is a nonsense variant, NP_000537.3:p.(Tyr103Ter)/p.(Y103*), not a missense, intronic, splice-region, or synonymous variant. The TP53 VCEP BP4 specification covers missense variants, single-amino-acid in-frame deletions, and silent or intronic variants, but not truncating nonsense variants; therefore SpliceAI 0.098 and BayesDel 0.66 were not evaluated for BP4. No exact entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt or PP3-BP4-codes.xlsx.txt. The single-amino-acid deletion table contains the different variant p.Tyr103del, not this nonsense variant.
Rule
TP53 VCEP BP4 is not applicable to a nonsense/truncating variant.
Evidence considered
The case normalization identifies NM_000546.5:c.309C>A as NP_000537.3:p.(Tyr103Ter)/p.(Y103*), with consequence class nonsense.
The TP53 VCEP Version 2.4 BP4 rule applies to missense variants, single-amino-acid in-frame deletions, and silent or intronic variants; it does not apply to nonsense variants.
The governing VCEP files were searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact target entry was found in the PP3/BP4 flowchart or lookup table, while the deletion table lists the different p.Tyr103del variant.
Still missing
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in PP3-BP4-codes.xlsx.txt.
No exact target entry found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; it contains the distinct p.Tyr103del variant.
BP5VCEPNot applicable: the TP53 VCEP explicitly marks BP5 as not applicable for this gene.
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Reasoning
The TP53 VCEP explicitly marks BP5 as not applicable. No TP53 VCEP BP5 rule is available for this variant, and no generic BP5 rule may override the governing gene-specific specification.
VCEP rule
TP53 VCEP BP5: Not applicable.
Evidence considered
The TP53 VCEP specification lists BP5 as Not Applicable.
BP6VCEPNot applicable: the TP53 VCEP prohibits BP6, and ClinVar has no exact-variant benign expert-panel classification.
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Reasoning
The TP53 VCEP explicitly marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact ClinVar record has no benign or likely-benign expert-panel classification; it contains only Pathogenic clinical-laboratory submissions. BP6 is therefore not applicable.
VCEP rule
TP53 VCEP BP6 is not applicable; an exact-variant ClinVar expert-panel Benign or Likely Benign classification would otherwise be required by the requested adjudication policy.
Evidence considered
The TP53 VCEP BP6 specification states: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The exact ClinVar record contains three Pathogenic clinical-laboratory submissions and zero expert-panel submissions, with no benign or likely-benign expert-panel assertion.
BP7N/ANot applicable: p.(Y103*) is a nonsense variant, whereas TP53 VCEP BP7 is limited to synonymous or qualifying intronic variants.
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Reasoning
Not applicable: NM_000546.5:c.309C>A is a nonsense variant, NP_000537.3:p.(Tyr103Ter)/p.(Y103*), not a synonymous variant. The TP53 VCEP BP7 specification is limited to synonymous silent or qualifying intronic variants, so the available SpliceAI max delta of 0.098 was not evaluated for BP7. No exact entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt, PP3-BP4-codes.xlsx.txt, or TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
Rule
TP53 VCEP BP7 is not applicable to a nonsense/truncating variant.
Evidence considered
The case normalization identifies NM_000546.5:c.309C>A as NP_000537.3:p.(Tyr103Ter)/p.(Y103*), with consequence class nonsense.
The TP53 VCEP Version 2.4 BP7 rule applies to synonymous silent or qualifying intronic variants, not nonsense variants.
The three declared governing VCEP text files were searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact target entry was found.
Still missing
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in PP3-BP4-codes.xlsx.txt.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TP53—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat +8 bp
0.038
SpliceAI acceptor gainat -4 bp
0.004
SpliceAI donor lossat -66 bp
0.014
SpliceAI donor gainat +134 bp
0.098
Pangolin splice lossmagnitude shown
-0.203
Pangolin splice gain
0.032
Other predictors
REVEL
Not available
BayesDel
0.660
How the predictions were used
PP3N/ANot applicable: p.(Y103*) is a nonsense variant, outside TP53 VCEP PP3 scope for missense, splice-region, intronic, or synonymous variants.
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Reasoning
Not applicable: NM_000546.5:c.309C>A is a nonsense variant, NP_000537.3:p.(Tyr103Ter)/p.(Y103*), not a missense, intronic, splice-region, or synonymous variant. The TP53 VCEP PP3 specification covers missense variants, single-amino-acid in-frame deletions, and exonic or intronic splice variants, but not truncating nonsense variants; therefore SpliceAI 0.098 and BayesDel 0.66 were not evaluated for PP3. No exact entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt or PP3-BP4-codes.xlsx.txt. The single-amino-acid deletion table contains the different variant p.Tyr103del, not this nonsense variant.
Rule
TP53 VCEP PP3 is not applicable to a nonsense/truncating variant.
Evidence considered
The case normalization identifies NM_000546.5:c.309C>A as NP_000537.3:p.(Tyr103Ter)/p.(Y103*), with consequence class nonsense.
The TP53 VCEP Version 2.4 PP3 rule applies to missense variants, single-amino-acid in-frame deletions, and exonic or intronic splice variants; it does not apply to nonsense variants.
The governing VCEP files were searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact target entry was found in the PP3/BP4 flowchart or lookup table, while the deletion table lists the different p.Tyr103del variant.
Still missing
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in PP3-BP4-codes.xlsx.txt.
No exact target entry found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; it contains the distinct p.Tyr103del variant.
BP4N/ANot applicable: p.(Y103*) is a nonsense variant, outside TP53 VCEP BP4 scope for missense, splice-region, intronic, or synonymous variants.
Details ▾Hide ▴
Reasoning
Not applicable: NM_000546.5:c.309C>A is a nonsense variant, NP_000537.3:p.(Tyr103Ter)/p.(Y103*), not a missense, intronic, splice-region, or synonymous variant. The TP53 VCEP BP4 specification covers missense variants, single-amino-acid in-frame deletions, and silent or intronic variants, but not truncating nonsense variants; therefore SpliceAI 0.098 and BayesDel 0.66 were not evaluated for BP4. No exact entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt or PP3-BP4-codes.xlsx.txt. The single-amino-acid deletion table contains the different variant p.Tyr103del, not this nonsense variant.
Rule
TP53 VCEP BP4 is not applicable to a nonsense/truncating variant.
Evidence considered
The case normalization identifies NM_000546.5:c.309C>A as NP_000537.3:p.(Tyr103Ter)/p.(Y103*), with consequence class nonsense.
The TP53 VCEP Version 2.4 BP4 rule applies to missense variants, single-amino-acid in-frame deletions, and silent or intronic variants; it does not apply to nonsense variants.
The governing VCEP files were searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact target entry was found in the PP3/BP4 flowchart or lookup table, while the deletion table lists the different p.Tyr103del variant.
Still missing
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in PP3-BP4-codes.xlsx.txt.
No exact target entry found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt; it contains the distinct p.Tyr103del variant.
BP7N/ANot applicable: p.(Y103*) is a nonsense variant, whereas TP53 VCEP BP7 is limited to synonymous or qualifying intronic variants.
Details ▾Hide ▴
Reasoning
Not applicable: NM_000546.5:c.309C>A is a nonsense variant, NP_000537.3:p.(Tyr103Ter)/p.(Y103*), not a synonymous variant. The TP53 VCEP BP7 specification is limited to synonymous silent or qualifying intronic variants, so the available SpliceAI max delta of 0.098 was not evaluated for BP7. No exact entry for c.309C>A, p.Tyr103Ter, or p.Y103* was found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt, PP3-BP4-codes.xlsx.txt, or TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
Rule
TP53 VCEP BP7 is not applicable to a nonsense/truncating variant.
Evidence considered
The case normalization identifies NM_000546.5:c.309C>A as NP_000537.3:p.(Tyr103Ter)/p.(Y103*), with consequence class nonsense.
The TP53 VCEP Version 2.4 BP7 rule applies to synonymous silent or qualifying intronic variants, not nonsense variants.
The three declared governing VCEP text files were searched for c.309C>A, p.Tyr103Ter, and p.Y103*; no exact target entry was found.
Still missing
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in Flowchart-for-application-of-PP3%2C-BP4%2C-and-BP7.pdf.txt.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in PP3-BP4-codes.xlsx.txt.
No exact c.309C>A, p.Tyr103Ter, or p.Y103* entry found in TP53-single-amino-acid-deletions-BayesDel-scores-(1).xlsx.txt.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.66.
9 paper records listed. 1 cited in the classification.
Cited in the classification
Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families.
Manoukian S et al. · 2007 Feb
This paper explicitly reports the TP53 germline nonsense variant c.309C>A (p.Y103X), corresponding to p.(Y103*), in family 2 and states that the alteration is predicted to result in protein truncation and is most likely deleterious.
Identified alterations included a nonsense (Y103X), a splice site (IVS4 + 1_IVS4 + 2insG) and a missense (R283C) mutation. All mutations are most likely deleterious. The first is predicted to result in protein truncation and the second to influence mRNA splicing.
Location Table 2, Family 2; Results, paragraph beginning "Identified alterations included a nonsense (Y103X)"
Context Twenty-three unrelated individuals from breast cancer/sarcoma families were screened using PCR amplification and direct sequencing of TP53 coding and non-coding exons, splice-site junctions, promoter, and 3' untranslated region.
Other recorded publications
A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.
This paper does not report TP53 c.309C>A or p.(Y103*); it studies 184 missense mutants in the carboxy-terminal tetramerization domain, residues 322–354, using oligomerization and transcriptional assays.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.
Kotler E et al. · 2018
This paper does not explicitly report TP53 c.309C>A or p.(Y103*); it describes a massively parallel functional scan of approximately 10,000 TP53 DNA-binding-domain variants in p53-null human cells, including a gene-level observation that premature termination codons strongly disrupt p53 functionality.
Notably, regardless of position along the DBD, premature termination codons and frameshift mutations resulted in a similarly strong disruption of p53 functionality
Results, ‘The Functional Impact of Distinct p53 Mutations Correlates with Protein Structural Domains and Evolutionary Conservation,’ paragraph 2; Figure 2A
Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.
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
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 2137911)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.66.
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 does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52663474, n = 16 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
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