17-7673836-C-T

Variant names:

• chr17-7673836-C-T
• rs200579969
• NM_000546.6:c.784G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2_Supporting PP3 BS2

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.784G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 262 (p.Gly262Ser). This variant received a total of 0.5 points in one individual (PS4 not met; Internal lab contributors). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor). This variant has an allele frequency of 0.00002358 (38/1611646 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.52, predicting that the variant has an impact on splicing (score threshold > 0.20) (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, PP3. (Bayesian Points: -2; VCEP specifications version 2.2; date of approval) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000416/MONDO:0018875/009

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: TP53 NM_000546.6 missense, splice_region
• Scores: Splicing: ADA: 0.9760
• Clinical Significance: Likely benign reviewed by expert panel U:8 B:1 O:1
• Conservation: PhyloP100: 7.91
• Publications: 59 publications found

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.784G>A	p.Gly262Ser	missense_variant, splice_region_variant	Exon 8 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.784G>A	p.Gly262Ser	missense_variant, splice_region_variant	Exon 8 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152048 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000817 AC: 2 AN: 244722 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1459598 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12 AN XY: 725972

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1110946

Other (OTH) AF: 0.0000663 AC: 4 AN: 60306

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152048 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:8 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Jan 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 262 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 are conflicting for this variant with the variant shown to be defective for transcriptional transactivation in yeast (PMID: 12826609) but functional in human cell growth suppression and proliferation assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 26534844, 32095738). This variant has been identified in 3/276106 chromosomes 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. -

Sep 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G262S variant (also known as c.784G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 784. The glycine at codon 262 is replaced by serine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387).This alteration has been reported in a BRCA1/2-negative woman diagnosed with breast cancer at age 42 and in her unaffected sister (Li J et al. J Med Genet. 2016 Jan;53(1):34-42) and also in a proband with breast cancer diagnosed at age 46 and 56 who underwent multigene panel testing (Bradbury AR et al. JCO Precis Oncol 2018 Apr;2). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jul 30, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:2

Jun 20, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The TP53 c.784G>A (p.Gly262Ser) variant involves the alteration of a conserved nucleotide located in the DNA binding domain, which is the target of 90% of p53 mutations found in human cancers (UMD database). 5/5 in silico tools predict a damaging outcome for this variant. This variant has been reported one family with multiple breast cancer patients, however, no detailed co-segregation analysis was performed. This variant has also been reported in numerous types of tumor samples with or without confirmed somatic status. This variant is absent in 89212 control chromosomes from ExAC. A reputable database (IARC) has reported this variant to have median transcription activity <=20% and classified it as non-functional. Other nearby missense variants have also been reported, namely p.Asn263Asp, p.Gly266Val and p.Arg267Trp; they all have been reported by a lab in ClinVar, the former two classified as uncertain significance and the last as likely pathogenic. One clinical diagnostic laboratory classified this variant as VUS. Taken together, this variant is currently classified as VUS-possibly pathogenic. -

May 12, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies are conflicting: non-functional transactivation, no effect on growth suppression (PMID: 29979965, 12826609, 30224644); Observed in an individual with breast cancer and her unaffected sister (PMID: 26534844); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8023157, 12826609, 7955036, 16907706, 10719737, 11161397, 14670539, 14559903, 9719952, 22768918, 22678923, 27564104, 20025891, 16818665, 15510160, 31016814, 30840781, 30352134, 29979965, 30224644, 26534844, 35328131, 30661751, 34273903, 32014905) -

Li-Fraumeni syndrome Uncertain:1 Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 262 of the TP53 protein (p.Gly262Ser). This variant is present in population databases (rs200579969, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 26534844, 32095738). ClinVar contains an entry for this variant (Variation ID: 141228). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Apr 03, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.784G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 262 (p.Gly262Ser). This variant received a total of 0.5 points in one individual (PS4 not met; Internal lab contributors). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributor). This variant has an allele frequency of 0.00002358 (38/1611646 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.52, predicting that the variant has an impact on splicing (score threshold > 0.20) (PP3). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, PP3. (Bayesian Points: -2; VCEP specifications version 2.2; date of approval) -

Adrenocortical carcinoma, hereditary Uncertain:1

Feb 26, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TP53-related disorder Uncertain:1

Apr 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TP53 c.784G>A variant is predicted to result in the amino acid substitution p.Gly262Ser. This variant has been reported in an individual with breast cancer as well as in an unaffected sibling (Figure 1, Li et al. 2016. PubMed ID: 26534844). An in silico quantitative model predicts this variant to be pathogenic (Table S1, Fortuno et al. 2019. PubMed ID: 30840781), but has also been predicted to be a variant of uncertain significance by another group (Evans et al. 2019. PubMed ID: 31016814). This variant is reported in 0.0024% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and has been reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141228/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Li-Fraumeni syndrome 1 Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 09-07-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.8	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.3	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Uncertain	0.0040	D;T;T;T;T;T;T;D;D;D;D;D;D;D;D;D;D;D;T
Polyphen		1.0, 1.0, 0.95	.;.;.;.;.;.;.;.;D;.;D;P;D;.;.;D;.;.;.
Vest4		0.89
MVP		0.99
MPC		0.38
ClinPred		0.99	D
GERP RS		5.0
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.75
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200579969; hg19: chr17-7577154; COSMIC: COSV52978722;