NM_000546.6(TP53):c.404G>A (p.Cys135Tyr) AND Li-Fraumeni syndrome

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Nov 7, 2025
Review status:: criteria provided, conflicting classifications

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:: RCV001069143.11

Allele description [Variation Report for NM_000546.6(TP53):c.404G>A (p.Cys135Tyr)]

NM_000546.6(TP53):c.404G>A (p.Cys135Tyr)

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.404G>A (p.Cys135Tyr)

HGVS:

NC_000017.11:g.7675208C>T
NG_017013.2:g.17343G>A
NM_000546.6:c.404G>AMANE SELECT
NM_001126112.3:c.404G>A
NM_001126113.3:c.404G>A
NM_001126114.3:c.404G>A
NM_001126115.2:c.8G>A
NM_001126116.2:c.8G>A
NM_001126117.2:c.8G>A
NM_001126118.2:c.287G>A
NM_001276695.3:c.287G>A
NM_001276696.3:c.287G>A
NM_001276697.3:c.-74G>A
NM_001276698.3:c.-74G>A
NM_001276699.3:c.-74G>A
NM_001276760.3:c.287G>A
NM_001276761.3:c.287G>A
NP_000537.3:p.Cys135Tyr
NP_000537.3:p.Cys135Tyr
NP_001119584.1:p.Cys135Tyr
NP_001119585.1:p.Cys135Tyr
NP_001119586.1:p.Cys135Tyr
NP_001119587.1:p.Cys3Tyr
NP_001119588.1:p.Cys3Tyr
NP_001119589.1:p.Cys3Tyr
NP_001119590.1:p.Cys96Tyr
NP_001263624.1:p.Cys96Tyr
NP_001263625.1:p.Cys96Tyr
NP_001263689.1:p.Cys96Tyr
NP_001263690.1:p.Cys96Tyr
LRG_321t1:c.404G>A
LRG_321:g.17343G>A
LRG_321p1:p.Cys135Tyr
NC_000017.10:g.7578526C>T
NM_000546.4:c.404G>A
NM_000546.5:c.404G>A
P04637:p.Cys135Tyr
p.C135Y

Protein change:

C135Y

Links:

UniProtKB: P04637#VAR_044756; dbSNP: rs587781991

Molecular consequence:

NM_001276697.3:c.-74G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-74G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-74G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.8G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.8G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.8G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.287G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Li-Fraumeni syndrome (LFS)
Synonyms:: Sarcoma family syndrome of Li and Fraumeni
Identifiers:: MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001234291	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 30, 2025)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 30630526, 12826609, 29979965, 30224644, 28492532
SCV006276546	Molecular Pathology, Peter Maccallum Cancer Centre See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV007449468	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 7, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001234291

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 30, 2025)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV006276546

Molecular Pathology, Peter Maccallum Cancer Centre

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 29, 2024)

germline

clinical testing

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

SCV007449468

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 7, 2025)

germline

clinical testing

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

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

Germline TP53 and MSH6 mutations implicated in sporadic triple-negative breast cancer (TNBC): a preliminary study.

Yi D, Xu L, Luo J, You X, Huang T, Zi Y, Li X, Wang R, Zhong Z, Tang X, Li A, Shi Y, Rao J, Zhang Y, Sang J.

Hum Genomics. 2019 Jan 10;13(1):4. doi: 10.1186/s40246-018-0186-y.

PubMed [citation]

PMID:: 30630526
PMCID:: PMC6327518

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

Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C.

Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Epub 2003 Jun 25.

PubMed [citation]

PMID:: 12826609
PMCID:: PMC166245

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001234291.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 135 of the TP53 protein (p.Cys135Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer at an allele fraction of 0.16 (PMID: 30630526). ClinVar contains an entry for this variant (Variation ID: 141762). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Molecular Pathology, Peter Maccallum Cancer Centre, SCV006276546.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital, SCV007449468.1

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

Description

Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1). This variant is predicted to alter protein function or structure, or disrupt splicing by multiple in silico tools (ACMG/AMP: PP3_Moderate).

#	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: Jul 27, 2026

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