NM_000546.6(TP53):c.380C>A (p.Ser127Tyr) AND Li-Fraumeni syndrome

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Sep 26, 2024
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:: RCV000813247.12

Allele description [Variation Report for NM_000546.6(TP53):c.380C>A (p.Ser127Tyr)]

NM_000546.6(TP53):c.380C>A (p.Ser127Tyr)

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.380C>A (p.Ser127Tyr)

HGVS:

NC_000017.11:g.7675232G>T
NG_017013.2:g.17319C>A
NM_000546.6:c.380C>AMANE SELECT
NM_001126112.3:c.380C>A
NM_001126113.3:c.380C>A
NM_001126114.3:c.380C>A
NM_001126115.2:c.-17C>A
NM_001126116.2:c.-17C>A
NM_001126117.2:c.-17C>A
NM_001126118.2:c.263C>A
NM_001276695.3:c.263C>A
NM_001276696.3:c.263C>A
NM_001276697.3:c.-98C>A
NM_001276698.3:c.-98C>A
NM_001276699.3:c.-98C>A
NM_001276760.3:c.263C>A
NM_001276761.3:c.263C>A
NP_000537.3:p.Ser127Tyr
NP_000537.3:p.Ser127Tyr
NP_001119584.1:p.Ser127Tyr
NP_001119585.1:p.Ser127Tyr
NP_001119586.1:p.Ser127Tyr
NP_001119590.1:p.Ser88Tyr
NP_001263624.1:p.Ser88Tyr
NP_001263625.1:p.Ser88Tyr
NP_001263689.1:p.Ser88Tyr
NP_001263690.1:p.Ser88Tyr
LRG_321t1:c.380C>A
LRG_321t2:c.380C>A
LRG_321:g.17319C>A
LRG_321p1:p.Ser127Tyr
NC_000017.10:g.7578550G>T
NM_000546.4:c.380C>A
NM_000546.5:c.380C>A
NM_001126112.2(TP53):c.380C>A
p.Ser127Tyr
NC_000017.11:g.7675232G>T

Protein change:

S127Y

Links:

dbSNP: rs730881999

NCBI 1000 Genomes Browser:

rs730881999

Molecular consequence:

NM_001126115.2:c.-17C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001126116.2:c.-17C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001126117.2:c.-17C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276697.3:c.-98C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-98C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-98C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.380C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.380C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.380C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.380C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.263C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.263C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.263C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.263C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.263C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000953598	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30224644, 12826609, 22109999, 29979965, 29470806, 28492532
SCV005425739	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 13, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 29979965, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000953598

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 26, 2024)

germline

clinical testing

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

SCV005425739

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Aug 13, 2024)

germline

clinical testing

PubMed (4)
[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	1	not provided	not provided	143475	not provided	clinical testing

Citations

PubMed

Assessment of p53 functional activity in tumor cells and histologically normal mucosa from patients with head and neck squamous cell carcinoma.

Van der Vorst S, Dekairelle AF, Weynand B, Hamoir M, Gala JL.

Head Neck. 2012 Nov;34(11):1542-50. doi: 10.1002/hed.21960. Epub 2011 Nov 23.

PubMed [citation]

PMID:: 22109999

Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.

Singh J, Thota N, Singh S, Padhi S, Mohan P, Deshwal S, Sur S, Ghosh M, Agarwal A, Sarin R, Ahmed R, Almel S, Chakraborti B, Raina V, DadiReddy PK, Smruti BK, Rajappa S, Dodagoudar C, Aggarwal S, Singhal M, Joshi A, Kumar R, et al.

Breast Cancer Res Treat. 2018 Jul;170(1):189-196. doi: 10.1007/s10549-018-4726-x. Epub 2018 Feb 22.

PubMed [citation]

PMID:: 29470806

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000953598.5

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

Description

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 127 of the TP53 protein (p.Ser127Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 656751). 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, 22109999, 29979965). This variant disrupts the p.Ser127 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29470806; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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

From All of Us Research Program, National Institutes of Health, SCV005425739.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces serine with tyrosine at codon 127 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant is defective in yeast transcriptional transactivation assays and human cell proliferation studies (PMID: 12826609, 29979965), but was inconclusive in human cell growth suppression assays (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. The variant has been observed in 10 tumors at cancerhotspots.org. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 16, 2025

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