rs146340390

Variant names:

• chr17-7674866-G-A
• rs146340390
• NM_000546.6:c.665C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7674866-G-A
• chr17-7674866-G-C
• chr17-7674866-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_000546.6(TP53):​c.665C>T​(p.Pro222Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P222P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:5
• Conservation: PhyloP100: 2.79

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
• BP6: Variant 17-7674866-G-A is Benign according to our data. Variant chr17-7674866-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161397.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=11}.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.665C>T	p.Pro222Leu	missense_variant	Exon 6 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.665C>T	p.Pro222Leu	missense_variant	Exon 6 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251328 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461814 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000716 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Oct 15, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.665C>T (p.Pro222Leu) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251328 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.665C>T has been reported in the literature in individuals affected with suspected Li-Fraumeni Syndrome, suspected Lynch syndrome, and leukemia (Yurgelun_2015, Ruijs_2010, Qian_2018, Wang_2013). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The variant was reported as functional in several experimental studies (ie. Kato_2003, Doffe_2020). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters classified the variants as VUS while three classified as likely benign/benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Dec 12, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TP53 c.665C>T; p.Pro222Leu variant (rs146340390) is reported in the literature in several individuals suspected of having Li-Fraumeni syndrome (Ruijs 2010) or Lynch syndrome (Yurgelun 2015), though it was also found in an individual not selected for a history of cancer (de Andrade 2017). This variant is reported in ClinVar (Variation ID: 161397) and is found on six chromosomes in the Genome Aggregation Database. The proline at codon 222 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. In functional assays, the p.Pro222Leu variant exhibits comparable transcriptional activation activity to wildtype protein (Grochova 2008, Slovackova 2010). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: de Andrade KC et al. Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. Hum Mutat. 2017 Dec;38(12):1723-1730. Grochova D et al. Analysis of transactivation capability and conformation of p53 temperature-dependent mutants and their reactivation by amifostine in yeast. Oncogene. 2008 Feb 21;27(9):1243-52. Ruijs MW et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet. 2010 Jun;47(6):421-8. Slovackova J et al. Transactivation by temperature-dependent p53 mutants in yeast and human cells. Cell Cycle. 2010 Jun 1;9(11):2141-8. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2 Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 26, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TP53 c.665C>T (p.Pro222Leu) variant has been reported in the published literature in individuals and families with suspected Li-Fraumeni syndrome (LFS) (PMIDs: 25980754 (2015), 20522432 (2010)), as well as LFS related cancers such as breast cancer (PMIDs: 34284872 (2022), 35323354 (2022), 33471991 (2021), 31159747 (2019), 25742471 (2015)). Additionally, this variant has been seen in individuals with acute lymphocytic leukemia (ALL) (PMID: 29300620 (2018)), chronic lymphocytic leukemia (CLL) (PMID: 21232794 (2011)), and glioblastoma (PMID: 20504876 (2010)). The variant has been described as functional in experimental studies (PMIDs: 33257846 (2021), 29979965 (2018)), however in yeast and human cells, it's reported to produce a less effective protein (PMID: 23897043 (2013), 20505364 (2010)). The frequency of this variant in the general population, 0.000031 (4/129082 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jan 31, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21232794, 28745575, 20504876, 25742471, 29979965, 30582853, 25637381, 20522432, 20505364, 17724467, 25980754, 19336573, 26917275, 15781620, 14559903, 12909720, 28364582, 28492532, 12826609, 30352134, 28230820, 17311302, 30224644, 23897043, 28861920, 30840781, 31159747, 30588330, 23484829, 31439692) -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Sep 28, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 222 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Yeast and mammalian cell studies reported this variant to be functional, with some temperature-sensitive effects observed in yeast (PMID: 12826609, 15781620, 17724467, 20505364, 23897043, 29979965, 30224644). This variant has been reported in an individual with childhood-onset rhabdomyosarcoma (PMID: 20522432) and in an individual affected with early-onset breast cancer meeting the Chompret criteria (PMID: 35323354). This variant has also been observed in an individual affected with Li-Fraumeni syndrome who has a pathogenic p.Arg267Trp variant in the same gene (PMID: 23484829), and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 6/282714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Uncertain:1 Benign:2

Nov 20, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 222 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Yeast and mammalian cell studies reported this variant to be functional, with some temperature-sensitive effects observed in yeast (PMID: 12826609, 15781620, 17724467, 20505364, 23897043, 29979965, 30224644). This variant has been reported in an individual with childhood-onset rhabdomyosarcoma (PMID: 20522432) and in an individual affected with early-onset breast cancer meeting the Chompret criteria (PMID: 35323354). This variant has also been observed in an individual affected with Li-Fraumeni syndrome who has a pathogenic p.Arg267Trp variant in the same gene (PMID: 23484829), and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 6/282714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome 1 Uncertain:2

Apr 11, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Dec 18, 2015

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1

Aug 06, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TP53-related disorder Uncertain:1

Oct 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TP53 c.665C>T variant is predicted to result in the amino acid substitution p.Pro222Leu. This variant has been reported as a germline variant in a patient with Li-Fraumeni syndrome (Ruijs et al. 2010. PubMed ID: 20522432) and in two patients with chronic lymphocytic leukemia while being absent from controls (Bilous et al. 2016. PubMed ID: 28230820). However, pathogenicity was not clearly established. This variant has been observed in only 6 out of ~282,000 alleles in a large population database and has been reported in ClinVar with conflicting interpretations ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Squamous cell carcinoma of the head and neck Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.69	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-7.3	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0080	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Uncertain	0.0060	D;D;T;T;T;T;T;T;D;D;D;D;D;D;D;D;D;D;D;T;.
Polyphen		0.099	B;.;.;.;.;.;.;.;.;B;.;B;P;B;.;.;B;.;.;.;B
Vest4		0.64
MVP		0.98
MPC		0.71
ClinPred		0.82	D
GERP RS		3.0
Varity_R		0.26
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146340390; hg19: chr17-7578184; COSMIC: COSV52909202; COSMIC: COSV52909202;