NM_000546.6(TP53):c.422G>A (p.Cys141Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 28, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000128975.11

Allele description [Variation Report for NM_000546.6(TP53):c.422G>A (p.Cys141Tyr)]

NM_000546.6(TP53):c.422G>A (p.Cys141Tyr)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.422G>A (p.Cys141Tyr)

HGVS:

NC_000017.11:g.7675190C>T
NG_017013.2:g.17361G>A
NM_000546.6:c.422G>AMANE SELECT
NM_001126112.3:c.422G>A
NM_001126113.3:c.422G>A
NM_001126114.3:c.422G>A
NM_001126115.2:c.26G>A
NM_001126116.2:c.26G>A
NM_001126117.2:c.26G>A
NM_001126118.2:c.305G>A
NM_001276695.3:c.305G>A
NM_001276696.3:c.305G>A
NM_001276697.3:c.-56G>A
NM_001276698.3:c.-56G>A
NM_001276699.3:c.-56G>A
NM_001276760.3:c.305G>A
NM_001276761.3:c.305G>A
NP_000537.3:p.Cys141Tyr
NP_000537.3:p.Cys141Tyr
NP_001119584.1:p.Cys141Tyr
NP_001119585.1:p.Cys141Tyr
NP_001119586.1:p.Cys141Tyr
NP_001119587.1:p.Cys9Tyr
NP_001119588.1:p.Cys9Tyr
NP_001119589.1:p.Cys9Tyr
NP_001119590.1:p.Cys102Tyr
NP_001263624.1:p.Cys102Tyr
NP_001263625.1:p.Cys102Tyr
NP_001263689.1:p.Cys102Tyr
NP_001263690.1:p.Cys102Tyr
LRG_321t1:c.422G>A
LRG_321:g.17361G>A
LRG_321p1:p.Cys141Tyr
NC_000017.10:g.7578508C>T
NM_000546.4:c.422G>A
NM_000546.5:c.422G>A
P04637:p.Cys141Tyr
p.C141Y

Protein change:

C102Y

Links:

UniProtKB: P04637#VAR_005886; dbSNP: rs587781288

NCBI 1000 Genomes Browser:

rs587781288

Molecular consequence:

NM_001276697.3:c.-56G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-56G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-56G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.26G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.26G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.26G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172861	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10589545, 28975465, 31206626 Citation Link,
SCV002582604	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006059695	Department of Pathology and Laboratory Medicine, Sinai Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 22, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20522432, 21232794, 10589545, 11370630, 24256616, 20128691, 21343334, 16861262, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172861

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 28, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002582604

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 18, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV006059695

Department of Pathology and Laboratory Medicine, Sinai Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 22, 2019)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Expanding the spectrum of germline variants in cancer.

Siraj AK, Masoodi T, Bu R, Parvathareddy SK, Al-Badawi IA, Al-Sanea N, Ashari LH, Abduljabbar A, Alhomoud S, Al-Sobhi SS, Tulbah A, Ajarim D, Alzoman K, Aljuboury M, Yousef HB, Al-Dawish M, Al-Dayel F, Alkuraya FS, Al-Kuraya KS.

Hum Genet. 2017 Nov;136(11-12):1431-1444. doi: 10.1007/s00439-017-1845-0. Epub 2017 Oct 3.

PubMed [citation]

PMID:: 28975465

Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.

Weitzel JN, Neuhausen SL, Adamson A, Tao S, Ricker C, Maoz A, Rosenblatt M, Nehoray B, Sand S, Steele L, Unzeitig G, Feldman N, Blanco AM, Hu D, Huntsman S, Castillo D, Haiman C, Slavin T, Ziv E.

Cancer. 2019 Aug 15;125(16):2829-2836. doi: 10.1002/cncr.32083. Epub 2019 Jun 17.

PubMed [citation]

PMID:: 31206626
PMCID:: PMC7376605

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000172861.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.C141Y pathogenic mutation (also known as c.422G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 422. The cysteine at codon 141 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported several times in families either meeting diagnostic criteria for Li-Fraumeni syndrome (LFS) or in families with features suggestive of LFS (Zhou XP et al. Ann Neurol. 1999 Dec;46(6):913-6; Monti P et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8). This mutation is located in the DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity and reduced DNA-binding in yeast-based assays compared to wildtype p53 protein (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002582604.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System, SCV006059695.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

ClinVar

Relating variation to medicine