VCV000428884.18 - ClinVar

NM_000546.6(TP53):c.313G>A (p.Gly105Ser)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (2); Likely pathogenic (3)

5 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.313G>A (p.Gly105Ser)

Variation ID: 428884 Accession: VCV000428884.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7676056 (GRCh38) [ NCBI UCSC ] 17: 7579374 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 1, 2017	Feb 15, 2026	Sep 10, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.313G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Gly105Ser	missense
NM_001126112.3:c.313G>A	NP_001119584.1:p.Gly105Ser	missense
NM_001126113.3:c.313G>A	NP_001119585.1:p.Gly105Ser	missense
NM_001126114.3:c.313G>A	NP_001119586.1:p.Gly105Ser	missense
NM_001126118.2:c.196G>A	NP_001119590.1:p.Gly66Ser	missense
NM_001276695.3:c.196G>A	NP_001263624.1:p.Gly66Ser	missense
NM_001276696.3:c.196G>A	NP_001263625.1:p.Gly66Ser	missense
NM_001276760.2:c.196G>A
NM_001276760.3:c.196G>A	NP_001263689.1:p.Gly66Ser	missense
NM_001276761.3:c.196G>A	NP_001263690.1:p.Gly66Ser	missense
NC_000017.11:g.7676056C>T
NC_000017.10:g.7579374C>T
NG_017013.2:g.16495G>A
LRG_321:g.16495G>A

... more HGVS ... less HGVS

Protein change

G105S, G66S

Other names

Canonical SPDI

NC_000017.11:7676055:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA397844735 dbSNP: rs1060501195 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TP53		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3915	4016

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 18, 2022	RCV000492331.3
Li-Fraumeni syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 15, 2023	RCV001379190.10
Li-Fraumeni syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Jun 18, 2022	RCV002289669.2
Adrenal cortex carcinoma	Likely pathogenic (1)	no assertion criteria provided	-	RCV004003474.1
Adrenocortical carcinoma, hereditary	Pathogenic (1)	criteria provided, single submitter	Sep 10, 2025	RCV005860088.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Mar 17, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015))	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000581123.4 First in ClinVar: Jul 01, 2017 Last updated: Jul 01, 2017	Publications: PubMed (1) PubMed: 15381368 Comment: show <span style="font-size:12px">The p.G105S variant (also known as c.313G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 313. The glycine at codon 105 is replaced by serine, an amino acid with similar properties.<span style="font-family:arial,sans-serif">This alteration is located in the functionally critical DNA binding domain and has shown a loss of transactivation activity in yeast based functional studies (Kato S et al. <span style="font-family:arial,sans-serif">Proc<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Natl<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Acad<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">Sci USA<span style="font-family:arial,sans-serif">. 2003 Jul 8;100(14):8424-9). Although this specific alteration has not been reported in the literature, another alteration at this position (p.G105C) was reported in a family with classic Li-Fraumeni Syndrome, where the proband had three primary breast cancers by the age of 31, and a family history of early onset breast cancer and brain tumors (Bendig I et al., <span style="font-family:arial,sans-serif">Cancer Genet. <span style="font-family:arial,sans-serif">Cytogenet<span style="font-family:arial,sans-serif">.<span style="font-family:arial,sans-serif"> <span style="font-family:arial,sans-serif">2004 Oct; 154(1):22-6). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., <span style="font-family:arial,sans-serif">Science 1994 Jul; 265(5170):346-55). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT <span style="font-family:arial,sans-serif">in silico<span style="font-family:arial,sans-serif"> analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1

Likely pathogenic (Jun 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Genome-Nilou Lab Accession: SCV002582410.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Likely pathogenic (Jun 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Li-Fraumeni syndrome 1	Genome-Nilou Lab Accession: SCV002583072.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Sep 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Adrenocortical carcinoma, hereditary	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV006551819.1 First in ClinVar: Oct 12, 2025 Last updated: Oct 12, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 15, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Li-Fraumeni syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001576941.6 First in ClinVar: May 10, 2021 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 12826609‚ 29979965‚ 30224644‚ 30840781 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 105 of the TP53 protein (p.Gly105Ser). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (Invitae; external communications). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly105 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644, 30840781). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 428884). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Adrenocortical carcinoma	Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University Accession: SCV004046833.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: no Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: no

Comment:

The p.G105S variant (also known as c.313G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 313. The glycine at codon 105 is replaced by serine, an amino acid with similar properties.This alteration is located in the functionally critical DNA binding domain and has shown a loss of transactivation activity in yeast based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Although this specific alteration has not been reported in the literature, another alteration at this position (p.G105C) was reported in a family with classic Li-Fraumeni Syndrome, where the proband had three primary breast cancers by the age of 31, and a family history of early onset breast cancer and brain tumors (Bendig I et al., Cancer Genet. Cytogenet. 2004 Oct; 154(1):22-6). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., Science 1994 Jul; 265(5170):346-55). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 105 of the TP53 protein (p.Gly105Ser). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (Invitae; external communications). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly105 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644, 30840781). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 428884).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A quantitative model to predict pathogenicity of missense variants in the TP53 gene.	Fortuno C	Human mutation	2019	PMID: 30840781
Mutational processes shape the landscape of TP53 mutations in human cancer.	Giacomelli AO	Nature genetics	2018	PMID: 30224644
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.	Kotler E	Molecular cell	2018	PMID: 29979965
Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin.	Bendig I	Cancer genetics and cytogenetics	2004	PMID: 15381368
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.	Kato S	Proceedings of the National Academy of Sciences of the United States of America	2003	PMID: 12826609

Text-mined citations for rs1060501195 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026