rs149633775

chr17-7673773-G-Achr17-7673773-G-Cchr17-7673773-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 5P and 12B. PM1 PM5 PP3 BP6_Very_Strong BS2

The NM_000546.6(TP53):c.847C>T(p.Arg283Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00007 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:10 B:9 O:2
• Conservation: PhyloP100: 4.69

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000546.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7673772-C-GG is described in ClinVar as [Pathogenic]. Clinvar id is 3148626.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• BP6: Variant 17-7673773-G-A is Benign according to our data. Variant chr17-7673773-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127824.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-7673773-G-A is described in Lovd as [Pathogenic]. Variant chr17-7673773-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.847C>T	p.Arg283Cys	missense_variant	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.847C>T	p.Arg283Cys	missense_variant	8/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251440 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135894

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000684 AC: 100 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152100 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74312

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000182 Hom.: 1

Bravo AF: 0.0000718

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:10 Benign:9 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 03, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 05, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 06, 2021	- -

not specified Uncertain:3 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in multiple individuals with cancer who did not meet Li-Fraumeni diagnostic criteria, and as a somatic variant in at least 7 tumors (Faille 1994, Diller 1995, Rugge 2000, Prescott 2001, Keller 2004, Libe 2007, Manoukian 2007, Ryu 2007, Pekova 2011, Melhem-Bertandt 2012, Schulz 2012, Boyault 2012, Mitchell 2013, Yurgelun 2015, Brohl 2017). It has also been identified in 17/129154 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though in vitro functional studies provide some evidence that the p.Arg283Cys variant may impact protein function (Monti 2011, Pekova 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg283Cys variant is uncertain. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 11, 2019	Variant summary: TP53 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251440 control chromosomes (gnomAD). The observed variant frequency is approximately 2-folds over the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome (LFS) phenotype (4e-05), strongly suggesting that the variant is benign. c.847C>T has been reported in the literature in patients with CLL, early-onset colorectal cancer, breast cancer, gastric carcinoma, pancreatic, and brain tumor as a germline or somatic variant, but most of the patients did not fulfill LFS criteria (e.g. Gaidano_1994, Yurgelun_2015, Manoukian_2007, Keller_2004, Melhem-Bertrandt_2012, Mitchell_2013, Schulz_2012, Wang_2013, Abe_2019, Mai_2017, Momozawa_2018, Tsaousis_2019, Young_2018). In addition, one patient who was affected with metachronous breast cancers and a subsequent leiomyosarcoma carried TP53 c.847C>T variant and a pathogenic BRCA2 variant (p.Arg2394X); however TP53 c.847C>T did not segregate with disease in her family, as it was absent in an astrocytoma patient (Manoukian_2007). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Functional studies provide conflicting results ranging from no defect (human cell line) to partially defective in yeasts (Pekova_2011, Monti_2011, Jagosova_2012). In addition, the IARC database indicates the variant to be functional. Twelve ClinVar submissions (evaluation after 2014) cite the variant eleven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

not provided Benign:3 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 08-08-2017 by 1197. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2020	This variant is associated with the following publications: (PMID: 22652532, 19367569, 17289876, 25527155, 21343334, no PMID, 15173255, 30224644, 29979965, 31016814, 23018556, 22710932, 17224268, 25980754, 23894400, 24728327, 21288114, 21512767, 25637381, 19558493, 21232794, 16487937, 19714488, 11040944, 26086041, 24868540, 12826609, 11793474, 8198984, 9865903, 11391594, 17727479, 28125078, 28861920, 15580553, 8203469, 29785153, 29300620, 21761402, 30840781, 31159747, 30374176, 29945567, 31786208, 31749828, 33300245, 32658383) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TP53: PP3, PS4:Supporting, BS3:Supporting, BS2 -

Li-Fraumeni syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Mar 28, 2018	The TP53 variant designated as NM_000546.5:c.847C>T (p.Arg283Cys) is classified as unlikely to cause fully penetrant Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.005 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity in the context of Li-Fraumeni syndrome. Additionally, the familial germline TP53 variant was detected in a family member's breast tumor tissue without evidence of loss of heterozygosity. It was unclear whether there was a second hit. The absence of loss of heterozygosity in the tumor may provide some evidence that the TP53 variant is more likely to be benign. There have been many reports this variant in patients with cancer. Although it is clear that this variant does not cause classic Li-Fraumeni syndrome, we cannot rule out the possibility that this variant does cause some increased risk for breast and other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Mar 18, 2022	This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been reported in 3 probands meeting Chompret criteria (PS4_Supporting; internal laboratory contributor (SCV000183772.7). However, this variant has been observed in greater than 8 60+ year old females without a cancer diagnosis (BS2; internal laboratory contributors: SCV000183772.7, SCV000254640.10) and has been seen many times by VCEP lab contributors in individuals not meeting LFS criteria. Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). The TP53 VCEP reviewed the conflicting evidence (PP3 and PS4_Supporting) and felt it did not override the Likely Benign classification in this case. In summary, the TP53 VCEP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Supporting, PP3, BS3, BS2. -

Li-Fraumeni syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 19, 2015	- -

Neoplasm of stomach Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The TP53 p.Arg283Cys variant was identified in 14 of 16242 proband chromosomes (frequency: 0.0009) from individuals or families with gastric cancer, breast cancer, leiomyosarcoma, sarcoma, or colorectal cancer and was present in 2 of 23844 control chromosomes (frequency: 0.00008) from healthy individuals (Keller 2004, Manoukian 2007, Mitchell 2013, Momozawa 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs149633775) as "With Likely pathogenic allele", ClinVar (classified as likely benign by one submitter; as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters; and as likely pathogenic by one submitter), Cosmic (22x in breast, endometrium, pancreatic and other tissues ), and LOVD 3.0 (3x). The variant was identified in control databases in 24 of 277184 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The frequency of the variant in certain populations increases the likelihood that this is a low frequency, benign variant; it was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6466 chromosomes (freq: 0.0002), and European in 20 of 126682 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro studies of the variant provide conflicting data: the variant demonstrated weakly temperature-dependent activity, partial deficiency of activity, or activity similar to wild type (Jagosove 2012, Pekova 2011, Monti 2011). The variant was identified in a family meeting criteria for HBOC and Li Fraumeni-like syndrome along with a pathogenic BRCA2 variant (c.7408A>T, p.R2394X). The p.Arg283 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.89	D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.1	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.089, 0.034, 1.0	.;.;.;.;.;.;.;.;B;.;B;D;B;.;.;B;.;.;.
Vest4		0.74
MVP		0.99
MPC		0.43
ClinPred		0.31	T
GERP RS		4.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.86
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs149633775; hg19: chr17-7577091; COSMIC: COSV52676681; COSMIC: COSV52676681;