17-7673775-C-T

Position:

chr17-7673775-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PM1PM5PP3_StrongPP5BS2

The NM_000546.6(TP53):c.845G>A(p.Arg282Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,956 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:22U:11

Conservation

PhyloP100: 6.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7673776-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 17-7673775-C-T is Pathogenic according to our data. Variant chr17-7673775-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237956.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=11}. Variant chr17-7673775-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-7673775-C-T is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.845G>A	p.Arg282Gln	missense_variant	8/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.845G>A	p.Arg282Gln	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251444

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135892

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:22Uncertain:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 19, 2021	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.845G>A, in exon 8 that results in an amino acid change, p.Arg282Gln. This sequence change has been described in gnomAD with only one heterozygous individual from the Finnish sup-population (dbSNP rs730882008). The p.Arg282Gln change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg282Gln substitution appears to be damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in a female patient diagnosed at age one with neuroblastoma. This sequence change was reportedly inherited from one of her parents and the family history (a maternal aunt with lymphoma diagnosed at 44) was not highly suggestive of Li-Fraumeni syndrome (PMID:10864200). This variant has also been reported in individuals affected with breast cancer, lung cancer, and prostate cancer but without strong evidence for causality (PMID: 26976419, 26787237, 30450585). In one of the reported cases of prostate cancer, a likely pathogenic deletion in exon 13 of the PALB2 gene was also identified, providing supporting evidence for limited causality of the TP53 variant (PMID:30450585). This amino acid position is considered a TP53 mutation hotspot where several other amino acid changes have been reported in individuals and families with TP53-related cancers (p.Arg282Gly, p.rg282Pro, p.Arg282Leu, p.Arg282Trp) (PMIDs: 15850016, 27616075, 28975465, 1565143). Functional studies have shown no or partially disruptive effect of this variant on transactivation activity in yeast-based assays (PMID: 11429705, 11896595, 11920959, 12826609, 12909720, 12917626, 21343334) and no effect on the anti-proliferative function of TP53 protein in mammalian cell-based assays (PMID: 29979965, 30224644). In summary, the c.845G>A sequence change has been reported in the literature in individuals affected with a variety of cancers but not fulfilling classic Li-Fraumeni syndrome criteria. Additionally, functional evidences are inconclusive. Based on the overall available evidence, the clinical significance of the p.Arg282Gln in TP53 change remains unknown at this time and has been classified as variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2020	Variant summary: TP53 c.845G>A (p.Arg282Gln) results in a 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 4e-06 in 251444 control chromosomes (gnomAD). c.845G>A has been reported in the literature in individuals affected with a variety of cancers but not fulfilling the classic criteria of LFS or even the LFI (Li-Fraunemi Incomplete) criteria. In our review of the associated literature, the penetrance of Li-Fraumeni Syndrome (0.67) due to this variant appears to be lower than expected (0.8), therefore no conclusions can be drawn from these data. Specifically, this variant was observed in a patient with neuroblastoma and was reportedly inherited from one of her parents, but the family history (a female patient, diagnosed at age 1 with neuroblastoma, and a maternal aunt with lymphoma diagnosed at 44) was not suggestive of Li-Fraumeni syndrome (Chompret 2000). The variant has been also reported as germline variant in several other cancer patients, including lung-, breast-, prostate and colorectal cancer, but without strong evidence for causality (Meric-Bernstam_2016, Tung_2016, Monti_2007, Giri_2019, Stoltze_2018). In addition, in one of these reports a co-occurrence with another likely pathogenic variant has been reported (PALB2 exon 13 deletion; Giri_2019), providing supporting evidence for limited causality. Additional studies are needed to address the penetrance and cancer risks associated with TP53 pathogenic variation in patients outside LFS spectrum. Several publications reported experimental evidence evaluating an impact on protein function, and multiple yeast assays demonstrated that the variant decreased, but did not abolish the transactivation capacity of TP53 and has been reported as a partially deficient (PD) allele (e.g. Monti_2011, Andreotti_2011 , Resnick_2003, Shi_2002). On the other hand, further studies performed in yeast and in human cells, revealed that the variant could also result in a gain of function activity, by interfering with the function of other p53 family members and increasing the expression of genes involved in cell proliferation- and tumor formation (Monti_2003, Shi_2002, Cordani_2011). These data however do not allow unequivocal conclusions about the variant significance. Six other clinical diagnostic laboratories have submitted conflicting clinical-significance assements for this variant to ClinVar after 2014 (i.e. 4 calling it a VUS, while 2 classifying it as likely pathogenic). At-least two of these submissions reflect a re-evaluation from their original assessment in the pathogenic spectrum. Based on the overall evidence outlined above, the variant was re-classified from its initial assessment as Likely Pathogenic at our laboratory and has since retained its classification as a VUS-possibly pathogenic. -

Li-Fraumeni syndrome 1

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 26, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 25, 2017	The c.845G>A (p.Arg282Gln) variant in the TP53 gene has been reported as a germline change in two related individuals with a family history of cancer (PMID: 17606709). This variant has also been reported in individuals affected with breast cancer, lung cancer and neuroblastoma (PMID: 26976419, 26787237, 10864200). Experimental studies have shown that this missense change affects TP53 protein structure and function (PMID: 15982667, 19913028). A different pathogenic missense substitution at this codon (p.Arg282Trp) has been reported in multiple cancer patients (PMID: 1565143, 21059199, 21305319, 21761402, 22672556, 11370630, 25584008) suggesting that the arginine residue is critical for TP53 protein. Based upon the above evidence, this c.845G>A, p.Arg282Gln variant is classified as likely pathogenic. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	TP53: PM1, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2024	Identified in individuals with breast cancer, neuroblastoma, prostate cancer, or other tumors (PMID: 10864200, 25980754, 26787237, 26976419, 29324801, 32318955, 33008098, 32885271, 34863587, 35534704); Published functional studies demonstrate partially functional transactivation and retained growth suppression activity (PMID: 11429705, 12826609, 12909720, 21343334, 30224644, 29979965); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21674059, 15982667, 18059157, 18555592, 11429705, 12909720, 24324553, 10864200, 12917626, 26787237, 26976419, 29324801, 27276561, 29126202, 27895058, 27463065, 29979965, 32560038, 17606709, 21343334, 11920959, 27346245, 18559976, 22361592, 27323394, 24603336, 19913028, 28821955, 30720243, 30840781, 32318955, 31447099, 30450585, 30327374, 30224644, 26585234, 26230955, 25952993, 23246812, 22915647, 22186996, 21519010, 20972454, 20407015, 19171880, 18453682, 16818505, 12826609, 11896595, 28638988, 28597078, 31588562, 30823914, 11782540, 28387325, 25980754, 27680515, 26619011, 27959731, 30352134, 29058119, 34863587, 35647242, 32885271, 38392212, 34273903, 30675318, 37937776, 33008098, 33574475, 15510160, 35534704, 38933650) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 2023	The p.R282Q variant (also known as c.845G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a family in which the proband was diagnosed with neuroblastoma at 1 year of age and the proband's maternal aunt was diagnosed with lymphoma at 44 years of age (Chompret A et al. Br. J. Cancer. 2000 Jun;82(12):1932-1937). Functional studies conducted in yeast have demonstrated partially reduced transactivation activity compared to wild type (Campomenosi P et al. Oncogene. 2001 Jun;20:3573-9; Shi XB et al. Prostate. 2002 Apr;51:59-72; IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). Additional studies in human Saos-2 cell lines showed gain of function properties such as upregulation of several promoters, growth in soft agar, and an increase in DNA synthesis (Shi XB et al. Prostate. 2002 Apr;51:59-72). Crystal structural analysis predict this alteration may cause destabilization of the protein (Tu C et al. Acta Crystallogr. D Biol. Crystallogr. 2008 May;64:471-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This alteration has been detected in the literature and numerous times in our laboratory, however, never in a case that meets classic Li-Fraumeni syndorme or Chompret criteria (Ambry internal data). Although this alteration has not been detected in individuals with Li-Fraumeni syndrome, we can not rule out the possibility that it is a low penetrance risk allele. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 14, 2023	This missense variant replaces arginine with glutamine at codon 282 in the DNA binding domain 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 have shown no or partially disruptive effect of this variant on transactivation activity in yeast-based assays (PMID: 11429705, 11896595, 11920959, 12826609, 12909720, 12917626, 21343334) and no effect on the anti-proliferative function of TP53 protein in mammalian cell-based assays (PMID: 29979965, 30224644). This variant has been reported in an infant affected with neuroblastoma with history of lymphoma in her maternal aunt (PMID 10864200). This variant has been observed in an individual affected with lung cancer in his seventies, with family history of breast and prostate cancer in his siblings (PMID: 26787237). This variant has also been observed in individuals affected with breast cancer (PMID: 26976419) and glioneuronal tumor (PMID: 29058119), as well as in an individual affected with colorectal cancer with early-onset breast cancer history in her mother and maternal grandmother (PMID: 29324801). This variant has been identified in 1/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same amino acid position (p.Arg282Trp, p.Arg282Pro) are considered to be disease-causing (ClinVar variation ID: 12364, 376659), suggesting that arginine at this position is important for protein function. However, the available clinical and functional evidence is insufficient to determine the role of the p.Arg282Gln variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 282 of the TP53 protein (p.Arg282Gln). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 10864200, 17606709, 26787237, 26976419, 32318955). ClinVar contains an entry for this variant (Variation ID: 237956). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 11429705, 11896595, 12826609, 12909720, 12917626, 15982667, 19913028, 21343334, 29979965). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces arginine with glutamine at codon 282 in the DNA binding domain 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 have shown no or partially disruptive effect of this variant on transactivation activity in yeast-based assays (PMID: 11429705, 11896595, 11920959, 12826609, 12909720, 12917626, 21343334) and no effect on the anti-proliferative function of TP53 protein in mammalian cell-based assays (PMID: 29979965, 30224644). This variant has been reported in an infant affected with neuroblastoma with history of lymphoma in her maternal aunt (PMID 10864200). This variant has been observed in an individual affected with lung cancer in his seventies, with family history of breast and prostate cancer in his siblings (PMID: 26787237). This variant has also been observed in individuals affected with breast cancer (PMID: 26976419) and glioneuronal tumor (PMID: 29058119), as well as in an individual affected with colorectal cancer with early-onset breast cancer history in her mother and maternal grandmother (PMID: 29324801). This variant has been identified in 1/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same amino acid position (p.Arg282Trp, p.Arg282Pro) are considered to be disease-causing (ClinVar variation ID: 12364, 376659), suggesting that arginine at this position is important for protein function. However, the available clinical and functional evidence is insufficient to determine the role of the p.Arg282Gln variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Glioblastoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant tumor of breast

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The TP53 p.Arg282Gln variant was identified in 4 of 6032 proband chromosomes (frequency: 0.0007) from individuals or families with neuroblastoma, breast cancer, lung cancer, or Lynch syndrome (Chrompret 2000, Meric-Bernstam 2016, Tung 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs730882008 as "With Likely pathogenic, Pathogenic allele"), ClinVar (2x as pathogenic by Invitae and Ambry Genetics; 2x as likely pathogenic by ARUP Laboratories and Integrated Genetics/Laboratory Corporation of America; and 1x as uncertain significance by GeneDx), Cosmic (37x in Skin, Bone, Hematopoietic and lymphoid tissue, Upper aerodigestive tract or Large intestine), and the IARC TP53 Database (identified 2x in germline and 30x as somatic; classified as partially functional). The variant was not identified in the GeneInsight-COGR or LOVD 3.0 databases. The variant was identified in control databases in 2 of 277176 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 126670 chromosomes (freq: 0.000008) and Finnish in 1 of 25792 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or South Asian populations. Multiple studies using a yeast functional reporter assay have classified this variant as loss of function and concluded that this variant does not possess dominant negative activity (Hassan 2008, Shi 2002). The p.Arg282 residue is conserved across mammals and other organisms, and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Arg282Gln variant may impact the protein; this information alone is not predictive enough to assume pathogenicity. However, the residue is located in the DNA-binding domain of TP53 and the Arg282Gln variant has been shown to accelerate the protein unfolding rate, possibly facilitating loss of protein function (Butler 2005). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Neoplasm of the large intestine

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Papillary renal cell carcinoma type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian serous cystadenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pancreatic adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Non-Hodgkin lymphoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Jan 09, 2024

. According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PM1 (medium pathogenic): This rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), PP3 (supporting pathogenic): AGVGD: C35, BayesDEL:0.477696 Fortuno et al. 2019 high probabilty of pathogenicity (>99%), BS3 (supporting benign): Kato 2003: partially functional / Giacomelli 2018: unclassified / Kotler 2018: no LoF RFS score: -1,61029460421 [cutoff RFS score > −1.0 for LOF and RFS score < −1.0 for noLOF] -

Adrenocortical carcinoma, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.1

.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.7

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0

.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.

Vest4

0.69

MutPred

0.97

Loss of MoRF binding (P = 0.1571);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.1571);.;Loss of MoRF binding (P = 0.1571);Loss of MoRF binding (P = 0.1571);Loss of MoRF binding (P = 0.1571);.;.;Loss of MoRF binding (P = 0.1571);.;.;.;

MVP

0.97

MPC

0.38

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.96

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over