NM_000546.6(TP53):c.707A>G (p.Tyr236Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 19, 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:: RCV002365462.3

Allele description [Variation Report for NM_000546.6(TP53):c.707A>G (p.Tyr236Cys)]

NM_000546.6(TP53):c.707A>G (p.Tyr236Cys)

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.707A>G (p.Tyr236Cys)

HGVS:

NC_000017.11:g.7674256T>C
NG_017013.2:g.18295A>G
NM_000546.6:c.707A>GMANE SELECT
NM_001126112.3:c.707A>G
NM_001126113.3:c.707A>G
NM_001126114.3:c.707A>G
NM_001126115.2:c.311A>G
NM_001126116.2:c.311A>G
NM_001126117.2:c.311A>G
NM_001126118.2:c.590A>G
NM_001276695.3:c.590A>G
NM_001276696.3:c.590A>G
NM_001276697.3:c.230A>G
NM_001276698.3:c.230A>G
NM_001276699.3:c.230A>G
NM_001276760.3:c.590A>G
NM_001276761.3:c.590A>G
NP_000537.3:p.Tyr236Cys
NP_000537.3:p.Tyr236Cys
NP_001119584.1:p.Tyr236Cys
NP_001119585.1:p.Tyr236Cys
NP_001119586.1:p.Tyr236Cys
NP_001119587.1:p.Tyr104Cys
NP_001119588.1:p.Tyr104Cys
NP_001119589.1:p.Tyr104Cys
NP_001119590.1:p.Tyr197Cys
NP_001263624.1:p.Tyr197Cys
NP_001263625.1:p.Tyr197Cys
NP_001263626.1:p.Tyr77Cys
NP_001263627.1:p.Tyr77Cys
NP_001263628.1:p.Tyr77Cys
NP_001263689.1:p.Tyr197Cys
NP_001263690.1:p.Tyr197Cys
LRG_321t1:c.707A>G
LRG_321:g.18295A>G
LRG_321p1:p.Tyr236Cys
NC_000017.10:g.7577574T>C
NM_000546.4:c.707A>G
NM_000546.5:c.707A>G

Protein change:

Y104C

Links:

dbSNP: rs730882026

NCBI 1000 Genomes Browser:

rs730882026

Molecular consequence:

NM_000546.6:c.707A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.707A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.707A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.707A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.311A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.311A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.311A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.230A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.230A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.230A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.590A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002661575	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 23, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10753186, 21343334, 30076369, 30720243, 30840781, 9667734 Citation Link,
SCV004359990	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 19, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9667734, 12826609, 16827139, 17606709, 21343334, 29979965, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002661575

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 23, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004359990

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 19, 2023)

germline

clinical testing

PubMed (8)
[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

Citations

PubMed

High frequency in esophageal cancers of p53 alterations inactivating the regulation of genes involved in cell cycle and apoptosis.

Robert V, Michel P, Flaman JM, Chiron A, Martin C, Charbonnier F, Paillot B, Frebourg T.

Carcinogenesis. 2000 Apr;21(4):563-5.

PubMed [citation]

PMID:: 10753186

Identification and characterization of TP53 gene Allele Dropout in Li-Fraumeni syndrome and Oral cancer cohorts.

Haque MM, Kowtal P, Sarin R.

Sci Rep. 2018 Aug 3;8(1):11705. doi: 10.1038/s41598-018-30238-7.

PubMed [citation]

PMID:: 30076369
PMCID:: PMC6076284

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV002661575.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Y236C pathogenic mutation (also known as c.707A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 707. The tyrosine at codon 236 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in two unrelated Li-Fraumeni Syndrome families, including one with a history of osteosarcomas, leukemia, and kidney cancer (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9, Rines R et al., Carcinogenesis 1998 Jun; 19(6):979-84). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a dominant negative effect in yeast based assays (IARC TP53 database; 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, Robert V et al., Carcinogenesis 2000 Apr; 21(4):563-5). Studies conducted in human cell lines indicate this alteration 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). In addition, based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). Based on the available evidence, this alteration is classified as a pathogenic 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 Color Diagnostics, LLC DBA Color Health, SCV004359990.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces tyrosine with cysteine at codon 236 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant is defective in transcriptional transactivation studies, human cell proliferation and growth suppression assays, and nuclear cytoplasmic localization assays (PMID: 12826609, 16827139, 17606709, 21343334, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome (PMID: 9667734, 17606709). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	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

Last Updated: Mar 16, 2025

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