TP53c.422G>ALikely pathogenic

Print report

Variant interpretation report

TP53 c.422G>A, p.(Cys141Tyr)

NM_000546.5:c.422G>A NP_000537.3:p.(Cys141Tyr) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TP53

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen TP53 VCEP v2.4.0
Other laboratories (ClinVar): 5 Pathogenic · 2 Likely pathogenic
Pipeline record: 8 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): The TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) assigns PS3 to C141Y. Kato assay: Non-functional. Additional eligible assays: Funk — LOF, Giacomelli — LOF, Kotler — LOF. This satisfies the VCEP PS3 rule: 'Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays' (3 of 3 non-Kato assays show LOF), conferring PS3 (strong). The variant is non-functional across all tested platforms.
PM2 (supporting): PM2_Supporting is met per VCEP specifications. gnomAD v4.1 total allele frequency = 1.86e-6 (0.000186%), which is well below the VCEP cutoff of <0.00003 (0.003%). In the highest subpopulation (European non-Finnish), AF = 2.54e-6 with 3 alleles across 1,180,016 alleles (<0.00004). The variant is absent from gnomAD v2.1 and gnomAD-Canada. The VCEP requires PM2 to be applied at supporting level for TP53.
PP3 (moderate): The TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3_moderate to c.422G>A (p.Cys141Tyr). BayesDel score = 0.568676 (≥0.16), aGVGD Class C65, and SpliceAI max delta = 0.00 (no predicted splicing effect, so the missense in silico rules apply directly). This satisfies the VCEP PP3_moderate rule: aGVGD Class C65 and BayesDel score ≥0.16. REVEL score = 0.897, consistent with a damaging prediction.

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 v2.4.0. 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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PS3Strong

PS3 · strong

The TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) assigns PS3 to C141Y. Kato assay: Non-functional. Additional eligible assays: Funk — LOF, Giacomelli — LOF, Kotler — LOF. This satisfies the VCEP PS3 rule: 'Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays' (3 of 3 non-Kato assays show LOF), conferring PS3 (strong). The variant is non-functional across all tested platforms.

PM2Supporting

PM2 · supporting

PM2_Supporting is met per VCEP specifications. gnomAD v4.1 total allele frequency = 1.86e-6 (0.000186%), which is well below the VCEP cutoff of <0.00003 (0.003%). In the highest subpopulation (European non-Finnish), AF = 2.54e-6 with 3 alleles across 1,180,016 alleles (<0.00004). The variant is absent from gnomAD v2.1 and gnomAD-Canada. The VCEP requires PM2 to be applied at supporting level for TP53.

PP3Moderate

PP3 · moderate

The TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3_moderate to c.422G>A (p.Cys141Tyr). BayesDel score = 0.568676 (≥0.16), aGVGD Class C65, and SpliceAI max delta = 0.00 (no predicted splicing effect, so the missense in silico rules apply directly). This satisfies the VCEP PP3_moderate rule: aGVGD Class C65 and BayesDel score ≥0.16. REVEL score = 0.897, consistent with a damaging prediction.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 moderate (+2) = 7 points, which maps to Likely Pathogenic.

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

3 / 1,614,148 alleles

gnomAD v4.1: 3 / 1,614,148 alleles. Recorded AF 1.85857e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

7 reported laboratory submissions

5 Pathogenic · 2 Likely pathogenic.

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.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

182 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV52664953, n = 182 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 v2.4.0, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 6 not met · 7 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000546.5:c.422G>A (p.Cys141Tyr) is a missense variant in exon 5 of TP53.

This variant is extremely rare in population databases: gnomAD v4.1 total allele frequency = 1.86e-6 (3/1,614,148 alleles), meeting PM2_Supporting (VCEP threshold <0.00003). It is absent from gnomAD v2.1 and gnomAD-Canada.

Functional studies demonstrate complete loss of function. The variant is non-functional in the Kato transactivation assay, and all additional eligible assays (Funk, Giacomelli, Kotler) show LOF, satisfying PS3 (strong) per TP53 VCEP specifications.

In silico predictions strongly support a deleterious effect: BayesDel score = 0.568676, aGVGD Class C65, REVEL = 0.897. The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.422G>A.

SpliceAI predicts no splicing impact (max delta = 0.00), confirming this variant is assessed as a missense change without splicing aberration.

The variant has been reported in ClinVar as Pathogenic by 5 clinical laboratories and Likely Pathogenic by 2, and has been observed 182 times in COSMIC somatic cancer database.

Combined Tavtigian point score (TP53 VCEP v2.4.0): PS3 (strong) = +4, PP3_moderate = +2, PM2_Supporting = +1. Total = +7 points, which falls in the Likely Pathogenic range (6-9 points).

Additional criteria (PS4, PS2, PP1) could not be assessed due to lack of proband-level cancer phenotype data, de novo observations, and cosegregation data in the available evidence. If PS4 evidence becomes available with ≥4 points (≥1 proband with strongly associated LFS cancer), the total would reach ≥10 points, reclassifying the variant as Pathogenic.

Met · 3

PS3 StrongThe TP53 VCEP Functional-worksheet.xlsx (Supplementary Table S3) assigns PS3 to C141Y. Kato assay: Non-functional. Additional eligible assays: Funk — LOF, Giacomelli — LOF, Kotler — LOF. This satisfies the VCEP PS3 rule: 'Non-functional on Kato et al. data AND loss of function (LOF) by the majority of other eligible assays' (3 of 3 non-Kato assays show LOF), conferring PS3 (strong). The variant is non-functional across all tested platforms. Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet.xlsx assigns PS3 for C141Y
Kato assay (PMID:12826609): Non-functional
Funk assay: LOF
Giacomelli assay (PMID:30224644): LOF
Kotler assay (PMID:29979965): LOF
Majority of eligible assays (3/3 non-Kato) show LOF

Sources

vcep_functional_worksheetPMID:12826609 ↗128266093022464429979965

PM2 SupportingPM2_Supporting is met per VCEP specifications. gnomAD v4.1 total allele frequency = 1.86e-6 (0.000186%), which is well below the VCEP cutoff of <0.00003 (0.003%). In the highest subpopulation (European non-Finnish), AF = 2.54e-6 with 3 alleles across 1,180,016 alleles (<0.00004). The variant is absent from gnomAD v2.1 and gnomAD-Canada. The VCEP requires PM2 to be applied at supporting level for TP53. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: AF = 1.86e-6 (3/1
614
148 alleles
0 homozygotes)
gnomAD v4.1 grpmax FAF = 6.8e-7 (European non-Finnish: 3/1
180
016)
gnomAD v2.1: absent
gnomAD-Canada: absent
Total AF <0.00003 (VCEP PM2_Supporting threshold)

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

PP3 ModerateThe TP53 VCEP PP3-BP4-codes.xlsx (Supplementary Table S2) assigns PP3_moderate to c.422G>A (p.Cys141Tyr). BayesDel score = 0.568676 (≥0.16), aGVGD Class C65, and SpliceAI max delta = 0.00 (no predicted splicing effect, so the missense in silico rules apply directly). This satisfies the VCEP PP3_moderate rule: aGVGD Class C65 and BayesDel score ≥0.16. REVEL score = 0.897, consistent with a damaging prediction. Details ▾Hide ▴

Evidence considered

VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.422G>A
BayesDel score = 0.568676 (≥0.16)
aGVGD Class C65 (most pathogenic class)
SpliceAI max delta = 0.00 (no splicing effect — missense rules apply)
REVEL = 0.897 (damaging)

Sources

vcep_pp3_bp4_codesbayesdelrevelspliceai ↗

Not met · 6 · evaluated, threshold not reached

PM1 PM1 is not met. Codon 141 is not one of the six VCEP-defined hotspot codons (175, 245, 248, 249, 273, 282). The alternative cancerhotspots.org pathway requires the same amino acid change (C141Y) to have ≥10 somatic occurrences (Moderate) or 2-9 (Supporting). The exact variant C141Y is not individually listed in cancerhotspots.org (exact_variant_listed: 'no'); the residue-level hotspot signal alone does not satisfy the VCEP PM1 rule which requires the specific amino acid change count. Details ▾Hide ▴

Evidence considered

Codon 141 is not among VCEP hotspot codons (175
245
248
249
273
282)
Cancer Hotspots: residue C141 is significant
but exact C141Y variant is not individually listed
COSMIC: n=182 occurrences but includes somatic + germline
not the VCEP-specified cancerhotspots.org source

Sources

cspec ↗

PM5 PM5 is not met. The pipeline searched for other missense variants at codon 141 (Cys) classified as Pathogenic or Likely Pathogenic per TP53 VCEP specifications. Zero qualifying comparator variants were identified. PM5_Strong requires ≥2 different pathogenic missense variants at the same residue; PM5_Moderate requires 1 pathogenic; PM5_Supporting requires 1 likely pathogenic with clinical data. None were found. Details ▾Hide ▴

Evidence considered

PM5 candidate search: 0 same-residue candidates found
0 expert panel P/LP candidates at codon 141
No VCEP-classified comparator variants at codon 141

Sources

pm5_candidates

BA1 BA1 is not met. The VCEP BA1 threshold requires filtering allele frequency (FAF) ≥0.001 (0.1%) in a gnomAD continental subpopulation with ≥2,000 alleles and ≥2 alleles present (excluding founder populations). gnomAD v4.1 grpmax FAF = 6.8e-7, four orders of magnitude below the BA1 threshold. The variant is extremely rare in all populations. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 6.8e-7 (far below BA1 threshold of ≥0.001)
European non-Finnish: 3 alleles in 1
180
016 — AF = 2.54e-6

Sources

gnomad_v4 ↗cspec ↗

BS1 BS1 is not met. The VCEP BS1 threshold requires FAF ≥0.0003 (0.03%) but <0.001 in a qualifying gnomAD subpopulation. gnomAD v4.1 grpmax FAF = 6.8e-7, approximately three orders of magnitude below the BS1 lower bound. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 grpmax FAF = 6.8e-7 (far below BS1 threshold of ≥0.0003)

Sources

gnomad_v4 ↗cspec ↗

BS3 BS3 is not met. The TP53 VCEP Functional-worksheet.xlsx assigns PS3 (not BS3) for C141Y. The variant is non-functional on Kato and shows LOF across all tested eligible assays (Funk, Giacomelli, Kotler). Per VCEP rules, BS3 requires functional or partially functional status on Kato AND no LOF by the majority of available assays — the opposite of what is observed. Functional evidence supports pathogenicity, not benign effect. Details ▾Hide ▴

Evidence considered

VCEP Functional-worksheet.xlsx assigns PS3
not BS3
for C141Y
Kato: Non-functional (does not satisfy BS3 threshold)
Funk: LOF
Giacomelli: LOF
Kotler: LOF

Sources

vcep_functional_worksheetPMID:12826609 ↗12826609

BP4 BP4 is not met. The VCEP PP3-BP4-codes.xlsx assigns PP3_moderate to c.422G>A, which precludes BP4. BayesDel score = 0.568676, far above the BP4_Supporting threshold (<0.16 and >-0.008) and the BP4_Moderate threshold (≤-0.008). SpliceAI max delta = 0.00 (no predicted splicing effect). The variant is strongly predicted damaging by all in silico tools. Details ▾Hide ▴

Evidence considered

VCEP assigns PP3_moderate — incompatible with BP4
BayesDel = 0.568676 (well above all BP4 thresholds)
aGVGD Class C65 (most pathogenic)

Sources

vcep_pp3_bp4_codesbayesdelspliceai ↗

Not assessed · 7 · no assessment recorded

PS1 PS1 requires a different nucleotide change at the same codon that produces the identical amino acid change (e.g., c.421T>A also yields p.Cys141Tyr) and has been previously classified as Pathogenic or Likely Pathogenic per TP53 VCEP specifications. No such comparator variant was identified in the available evidence. Without a qualifying comparator, PS1 cannot be applied. Details ▾Hide ▴

Evidence considered

c.421T>A (also p.Cys141Tyr) could theoretically serve as a comparator but was not assessed per VCEP specifications in the available evidence

Still missing

Need VCEP classification status of c.421T>A (p.Cys141Tyr) as a potential PS1 comparator

PS2 No de novo evidence was identified for this variant. The exploratory evidence search for PS2 did not return results within the available timeframe. No papers with confirmed de novo observations of c.422G>A were found in full-text review. The VCEP PS2 scoring system (1 pt = Supporting, 2-3 pts = Moderate, 4-7 pts = Strong, ≥8 pts = Very Strong) requires proband cancer data with LFS-associated phenotypes. Details ▾Hide ▴

Evidence considered

Exploratory search for de novo observations timed out — no results returned

Still missing

De novo observations of c.422G>A with LFS cancer phenotypes in probands

PS4 PS4 requires proband counts with LFS-associated cancer phenotypes to calculate points per the VCEP PS4-Points-Table (strongly associated cancers = 4 pts, moderately associated = 2 pts per proband). The variant has been reported in ClinVar as Pathogenic by 5 clinical laboratories and Likely Pathogenic by 2, citing papers including PMID:10589545 and PMID:11370630. However, the specific variant was not confirmed in any available full-text publication. Without verified proband-level cancer phenotype data, PS4 points cannot be calculated. Details ▾Hide ▴

Evidence considered

ClinVar: Pathogenic (5 labs)
Likely Pathogenic (2 labs)
ClinVar submits PMID:10589545
PMID:11370630
PMID:20522432 as clinical observation references
Exploratory evidence search timed out without returning proband-level data

Still missing

Proband-level cancer phenotype data with LFS-associated cancers
Verification of variant mention in PMID:10589545 (glioma families)
PMID:11370630 (LFS families)
PMID:20522432 (LFS families)

Sources

clinvar ↗

PP1 No cosegregation data is available for this variant. PP1 per VCEP requires observed cosegregation in 3-4 meioses (Supporting), 5-6 meioses (Moderate), or ≥7 meioses (Strong) across one or more families. No family pedigree or segregation studies mentioning c.422G>A were identified in the available evidence. The exploratory search for PP1 did not return results. Details ▾Hide ▴

Evidence considered

Exploratory search for cosegregation data timed out — no results returned

Still missing

Family pedigree data with cosegregation of c.422G>A and LFS cancers across meioses

PP4 No variant allele fraction (VAF) data is available to assess PP4. The VCEP PP4 rule requires observation of the variant with VAF 5-35% (Supporting) or ≥2 independent observations with VAF 5-25% (Moderate), as a surrogate for constitutional mosaicism or clonal hematopoiesis assessment. No VAF data for c.422G>A was found in the evidence. Details ▾Hide ▴

Evidence considered

No VAF data available in evidence sources

Still missing

Variant allele fraction data from clinical testing reports

BS2 No data are available on healthy females ≥60 years of age without cancer who carry this variant. The VCEP BS2 rule requires ≥8 (Strong), 4-7 (Moderate), or 2-3 (Supporting) unrelated females aged ≥60 without cancer, all from a single source. No such observations were found in the evidence. Details ▾Hide ▴

Evidence considered

No data on healthy older female carriers in available evidence

Still missing

Observations of c.422G>A in healthy females ≥60 years without cancer

BS4 No segregation data demonstrating lack of segregation in affected family members is available. The VCEP BS4 rule requires observation of the variant not segregating with LFS-associated cancers in affected family members. The exploratory search for BS4 evidence did not return results. Details ▾Hide ▴

Evidence considered

Exploratory search for BS4/segregation evidence timed out — no results returned

Still missing

Segregation data showing lack of cosegregation with LFS cancers in affected families

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/APVS1 is not applicable to missense variants. This variant (c.422G>A, p.Cys141Tyr) is a missense substitution, not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The VCEP PVS1 flowchart applies only to null variants. SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴

Evidence considered

Missense variant p.Cys141Tyr — not a null variant
SpliceAI max delta = 0.00 — no predicted splicing impact
Variant bucket: other — does not fit PVS1 null-variant categories

Sources

spliceai ↗pvs1_variant_assessment

PM3 VCEPPM3 applies to recessive disorders where a variant is detected in trans with a pathogenic variant. TP53-associated Li-Fraumeni syndrome is an autosomal dominant condition; PM3 is not applicable. Details ▾Hide ▴

Evidence considered

Autosomal dominant inheritance — PM3 is for recessive disorders only

PM4 VCEPPM4 applies to in-frame deletions/insertions or stop-loss variants. c.422G>A is a missense substitution, not a protein-length-altering variant. VCEP also declares PM4 not applicable for TP53. Details ▾Hide ▴

Evidence considered

Missense substitution — PM4 is for in-frame indels and stop-loss variants only

Sources

cspec ↗

PM6 VCEPPM6 is declared not applicable by the TP53 VCEP v2.4.0. De novo evidence is assessed under the PS2 criterion per VCEP specifications. Details ▾Hide ▴

Evidence considered

VCEP specifications: PM6 applicability = Not Applicable

Sources

cspec ↗

PP2 VCEPPP2 is declared not applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴

Evidence considered

VCEP specifications: PP2 applicability = Not Applicable

Sources

cspec ↗

PP5 VCEPPP5 is declared not applicable by the TP53 VCEP v2.4.0. Per the VCEP: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴

Evidence considered

VCEP specifications: PP5 applicability = Not Applicable

Sources

cspec ↗

BP1 VCEPBP1 is declared not applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴

Evidence considered

VCEP specifications: BP1 applicability = Not Applicable

Sources

cspec ↗

BP2 VCEPBP2 is declared not applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴

Evidence considered

VCEP specifications: BP2 applicability = Not Applicable

Sources

cspec ↗

BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions without known function. c.422G>A is a missense substitution, not an in-frame indel. Details ▾Hide ▴

Evidence considered

Missense substitution — not an in-frame indel in a repetitive region

BP5 VCEPBP5 is declared not applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴

Evidence considered

VCEP specifications: BP5 applicability = Not Applicable

Sources

cspec ↗

BP6 VCEPBP6 is declared not applicable by the TP53 VCEP v2.4.0. Details ▾Hide ▴

Evidence considered

VCEP specifications: BP6 applicability = Not Applicable

Sources

cspec ↗

BP7 N/ABP7 is not applicable to missense variants. BP7 per VCEP applies only to synonymous (silent) variants outside the core splice motif or intronic variants at or beyond +7 to -21 positions for which SpliceAI predicts no splicing impact (≤0.1). This is a missense variant producing p.Cys141Tyr. Details ▾Hide ▴

Evidence considered

Missense variant p.Cys141Tyr — BP7 only applies to synonymous and intronic variants

Sources

cspec ↗spliceai ↗

PS5 N/APS5 (same amino acid change as a previously established pathogenic variant) is not defined in the TP53 VCEP v2.4.0 criteria. The VCEP subsumes same-residue comparator logic under PM5 (different missense at same residue) and PS1 (same amino acid via different nucleotide change). No PS5 rules exist in the VCEP framework. Details ▾Hide ▴

Evidence considered

PS5 is absent from the TP53 VCEP v2.4.0 criteria specification

Sources

cspec ↗

Identifiers

Gene: TP53
Transcript: NM_000546.5
Coding (HGVS c.): NM_000546.5:c.422G>A
Protein (HGVS p.): NP_000537.3:p.(Cys141Tyr)
GRCh38: chr17:7675190 C>T
GRCh37: chr17:7578508 C>T
ClinVar: 140801, 12366
COSMIC: COSV52664953

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…

Exons

—

Transcript span

—

Strand

—

Variants mapped

—

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 v4.1 3 / 1,614,148 alleles AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,614,148 alleles · 0 hom · FAF 6.8e-07

European (non-Finnish)3 / 1,180,016

2.5e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85857e-06; MAF= 0.00019%, 3/1614148 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54234e-06; MAF= 0.00025%, 3/1180016 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: 0.897
BayesDel: 0.569

How the predictions were used

Evidence considered

VCEP PP3-BP4-codes.xlsx assigns PP3_moderate for c.422G>A
BayesDel score = 0.568676 (≥0.16)
aGVGD Class C65 (most pathogenic class)
SpliceAI max delta = 0.00 (no splicing effect — missense rules apply)
REVEL = 0.897 (damaging)

Sources

vcep_pp3_bp4_codesbayesdelrevelspliceai ↗

Evidence considered

VCEP assigns PP3_moderate — incompatible with BP4
BayesDel = 0.568676 (well above all BP4 thresholds)
aGVGD Class C65 (most pathogenic)

Sources

vcep_pp3_bp4_codesbayesdelspliceai ↗

Evidence considered

Missense variant p.Cys141Tyr — BP7 only applies to synonymous and intronic variants

Sources

cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.897. BayesDel score = 0.568676.

11 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

A global suppressor motif for p53 cancer mutants.

No paper-specific finding is recorded.

PMID 15037740 ↗
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S et al. · 2003

No paper-specific finding is recorded.

PMID 12826609 ↗
Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.

Dearth LR et al. · 2007

No paper-specific finding is recorded.

PMID 16861262 ↗
Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation.

Malcikova J et al. · 2010

No paper-specific finding is recorded.

PMID 20128691 ↗
A comprehensive study of TP53 mutations in chronic lymphocytic leukemia: Analysis of 1287 diagnostic and 1148 follow-up CLL samples.

Pekova S et al. · 2011

No paper-specific finding is recorded.

PMID 21232794 ↗
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.

Monti P et al. · 2011

No paper-specific finding is recorded.

PMID 21343334 ↗
Identification of new p53 target microRNAs by bioinformatics and functional analysis.

Bisio A et al. · 2013

No paper-specific finding is recorded.

PMID 24256616 ↗
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.

No paper-specific finding is recorded.

PMID 25741868 ↗
National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers.

No paper-specific finding is recorded.

PMID 19042984 ↗
Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement.

No paper-specific finding is recorded.

PMID 22964825 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

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

gnomAD v4.1 3 / 1,614,148 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 5 Pathogenic · 2 Likely pathogenic 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

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Likely pathogenic (2 clinical laboratories). (ClinVarID = 140801)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.897. BayesDel score = 0.568676.

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; COSV52664953, n = 182 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.