17-7670699-C-T

Position:

chr17-7670699-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000269305.9(TP53):c.1010G>A(p.Arg337His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,858 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 pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27

Conservation

PhyloP100: 0.244

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 13 uncertain in ENST00000269305.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7670700-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 17-7670699-C-T is Pathogenic according to our data. Variant chr17-7670699-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7670699-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.1010G>A	p.Arg337His	missense_variant	10/11	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.1010G>A	p.Arg337His	missense_variant	10/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250846

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461744

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:27

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Apr 21, 2022	ACMG Criteria: PS3, PM2, PM5, PP3, PP5; Variant was found in heterozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28369373; 20407015) - PS3. The c.1010G>A;p.(Arg337His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12379; PMID: 20301488; 28387921; 28864397; 28984303; 28968711; 28756477; 30107858) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (P53_tetramer) - PM1. Pathogenic missense variant in this residue have been reported (ClinVar ID: 142536 - c.1009C>T;p.(Arg337Cys)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 14, 2021	ACMG classification criteria: PS3, PS4, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2021	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Li-Fraumeni syndrome

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Mar 06, 2020	Data included in classification: Multiple case reports of this variant in the literature in cases meeting Chompret criteria, due to its identification in children with adrenocortical cancer. 117 reports on IARC database (germline). (PS4_Strong). Variant is absent from 56,697 NFE gnomAD controls (N.B. present in 2 latino controls and 1 other but known to be a founder mutation in the Brazilian population) (PM2_sup). Variant predicted as deleterious by BayesDel 0.178 and AlignGVGD C25 (PP3_sup) Data not included in classification: 2* classification of pathogenic on ClinVar, multiple submitters Kato et al, 2003: variant is partially functional on yeast based assay (PMID: 12826609). Giacomelli et al 2008 (PMID: 30224644) no dominant negative activity or loss of function shown on functional studies. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 17, 2019	The p.Arg337His variant in TP53 has been reported in numerous individuals with Li-Fraumeni syndrome and is thought to be a founder allele in Southern Brazil (Achatz 2016, Andrade 2016, Borges 2016). Although cancers associated with this allele tend to occur at a later age compared to other pathogenic variants in TP53, the lifetime risk seems to be similar to other LFS-associated TP53 variants (Garritano 2010). This variant has also been reported in ClinVar (Variation ID 12379). It has been identified in 0.007% (2/24544) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additional variants involving this codon (p.Arg337Cys, p.Arg337Leu) have been identified in individuals with cancer and are classified as likely pathogenic/pathogenic by clinical laboratories in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PM2, PS4, PP1_strong, PP3, PM5. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with histidine at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the variant protein impacted protein stability and tetramerization, however, this defect may appear mild in some transactivation and growth inhibition assays (PMID: 9582268, 12826609, 20407015, 30224644; and IARC database). This variant is known to be a Brazilian founder mutation and observed in approximately 0.3% of the population in southern Brazil (PMID: 24936644, 27663983). This variant has been reported in numerous Brazilian individuals and families affected with Li-Fraumeni syndrome meeting Chompret criteria (PMID: 10864200, 16033918, 21192060, 27714481), Li-Fraumeni-like syndrome (PMID: 16494995), and early-onset breast cancer (PMID: 19046423, 22455664, 27223487). Studies of families carrying this variant have shown extremely variable cancer risk in individuals and identified several unaffected adult carriers, suggesting age-dependent (and possibly incomplete) penetrance of this variant (PMID: 19717094). This variant has been identified in 3/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg337Cys, p.Arg337Leu and p.Arg337Pro) have been reported as disease-causing in ClinVar (variation ID: 142536, 142828, 177879), suggesting that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 337 of the TP53 protein (p.Arg337His). This variant is present in population databases (rs121912664, gnomAD 0.006%). This missense change has been observed in individual(s) with multiple types of cancer (PMID: 10864200, 16033918, 16494995, 21192060, 23733769). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12379). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) did not meet the statistical confidence thresholds required to predict the impact of this variant on TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 9704930, 12826609, 20407015). This variant disrupts the p.Arg337 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9704931, 20407015). 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. -

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 07, 2022	The frequency of this variant in the general population, 0.000012 (3/250846 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a Brazilian founder mutation associated with reduced penetrance, carrying a lower cancer risk than other TP53 pathogenic variants (PMID: 33300245 (2021), 31744167 (2019), 19877175 (2009)). It has been reported in up to 0.2 to 0.3% of the Brazilian population (PMID: 32592449 (2049), 19717094 (2009)). This variant has been seen in individuals with breast cancer (PMID: 32986223 (2021), 32039725 (2020), 30596752 (2018), 22455664 (2012)), Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 30107858 (2018), 29392648 (2018), 28756477 (2018), 21192060 (2011)), and children with adrenocortical tumors (ACT) (PMID: 32156018 (2020), 31744167 (2019), 16033918 (2006), 16033918 (2006), 15121773 (2004), 11481490 (2001)). Some published functional studies are conflicting, but the majority have found that this variant causes a partial or conditional damaging effect on TP53 function (PMID: 35367578 (2022), 33637564 (2021), 30042151 (2018), 28369373 (2017), 23056559 (2012), 21343334 (2011), 20407015 (2010), 12826609 (2003), 11753428 (2002), 9704930 (1998)). Based on the available information, this variant is classified as a pathogenic variant with reduced penetrance. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2022	Founder variant present in 0.2-0.3% of the South Brazilian population (Garritano et al., 2010); Reported to result in lower cancer risks by early adulthood than variants associated with classic Li-Fraumeni syndrome, with a 21% risk of cancer reported by age 45 per one study, but comparable lifetime cancer risks (Garritano et al., 2010; Mastellaro et al., 2017); Published functional studies demonstrate a damaging effect: reduced ability to form tetramers resulting in reduced transactivation in a pH-dependent manner, increased tumorigenesis in a knock-in mouse model (DiGiammarino et al., 2002; Jordan et al., 2010; Park et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19717094, 10864200, 15121773, 23794094, 11753428, 28369373, 27866339, 30588330, 29039119, 30535581, 32592449, 31978118, 21343334, 11481490, 12826609, 21192060, 18248785, 22170717, 22455664, 16033918, 23259501, 23733769, 21445348, 9704930, 11600572, 25736369, 21468523, 19046423, 22004116, 23570263, 16750598, 24784157, 23056559, 24936644, 26452166, 19877175, 27223487, 27275664, 26656232, 27663983, 28387921, 27081505, 25945745, 26823150, 28114597, 28254861, 16494995, 28968711, 28152038, 28864397, 28724667, 28472496, 30774760, 27714481, 30596752, 29392648, 29928384, 30042151, 30107858, 31748977, 29625052, 32039725, 32671623, 33603772, 30224644, 32485079, 31744167, 31889631, 33138793, 31778928, 26681051, 31105275, 31494577, 20407015, 15510160, 33258288, 33637564, 32986223, 32817165, 29922827, 30982232, 32156018) -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, Catalan Institute of Oncology	May 19, 2023	c.1010G>A, located in exon 10 of the TP53 gene, is predicted to result in the substitution of Arginine by Histidine at codon 337, p.(Arg337His). This variant is found in 1/236428 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. This variant has a BayesDel score 0.17 and Align GVGD (Zebrafish) is Class C0. Transactivation assays show a partially function allele according to Kato 2003 (PMID: 12826609) and there is a second assay showing low function (tetramer assay, PMID: 18940924) (PS3_Moderate). At least, this variant has been reported in 33 Chompret individuals, which awards 16 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 10864200, 16933305, 18270399, 21630152, 21440489, 22619358, 28453760, 30147334, among others) (PS4). It has been observed cosegregation (7 meiosis) in three families (PMID: 11521785, 27101110, 29956451) (PP1_Strong). In addition, this variant has been identified de novo in 4 individuals (PMID: 27601191, 27101110, 32292755) (PM6_Very Strong). The variant is present in >3 living unaffected individuals above 55 years of age (PMID: 17940213, 18373486) (BS4). This variant is a founder in Brasil. It has been reported in ClinVar (15x as pathogenic, 1x as likely pathogenic), LOVD (2x as pathogenic, 2x NA), CancerHotspots (4 somatic observations). Based on the currently available information, c.1010G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 16, 2023	This missense variant replaces arginine with histidine at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the variant protein impacted protein stability and tetramerization, however, this defect may appear mild in some transactivation and growth inhibition assays (PMID: 9582268, 12826609, 20407015, 30224644; and IARC database). This variant is known to be a Brazilian founder mutation and observed in approximately 0.3% of the population in southern Brazil (PMID: 24936644, 27663983). This variant has been reported in numerous Brazilian individuals and families affected with Li-Fraumeni syndrome meeting Chompret criteria (PMID: 10864200, 16033918, 21192060, 27714481), Li-Fraumeni-like syndrome (PMID: 16494995), and early-onset breast cancer (PMID: 19046423, 22455664, 27223487). Studies of families carrying this variant have shown extremely variable cancer risk in individuals and identified several unaffected adult carriers, suggesting age-dependent (and possibly incomplete) penetrance of this variant (PMID: 19717094). This variant has been identified in 3/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg337Cys, p.Arg337Leu and p.Arg337Pro) have been reported as disease-causing in ClinVar (variation ID: 142536, 142828, 177879), suggesting that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 24, 2022	The p.R337H pathogenic mutation (also known as c.1010G>A) is located in coding exon 9 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 1010. The arginine at codon 337 is replaced by histidine, an amino acid with highly similar properties. There currently exists a relatively extensive body of literature regarding this alteration. It has been detected at high frequency in Brazilian LFS families and is highly associated with a common haplotype, providing strong evidence of a founder effect in this population (Garritano et al. Hum Mutat. 2010 Feb;31(2):143-50). Ribeiro and colleagues described p.R337H as a low-penetrance mutation, primarily associated with adrenal cortical tumor risk in childhood; another study identified this mutation at a high (12.1%) frequency in Brazilian women with early-onset breast cancer (Ribeiro RC et al. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9330-5; Giacomazzi J et al, PLoS ONE 2014 ; 9(6):e99893). Other studies have led authors to conclude that the lifetime cancer risks for carriers of this mutation are similar to those of other LFS families, although p.R337H-associated cancers tend to occur with a later age of onset (Garritano et al. Hum Mutat. 2010 Feb;31(2):143-50). Families with this mutation have been reported with a wide spectrum of tumors including, but not limited to, breast cancers, brain cancers, soft tissue sarcomas, and adrenocortical carcinoma (Achatz et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Borges LM and Avres FM. Genet Mol Res. 2015 Dec 16;14(4):17034-43; IARC Database http://www-p53.iarc.fr/; Andrade RC et al. Fam. Cancer. 2017 Apr;16(2):243-248; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). One functional study demonstrated that the reduction in transcriptional activity and DNA binding resulting from this amino acid substitution is similar to that observed in null mutations (Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). In addition, this amino acid substitution occurs within the protein tetramerization domain and alters the ability of p53 to form stabilizing oligomers with high DNA-binding capacity in cells with elevated pH levels. This pH dependence may explain the incomplete penetrance observed in many families carrying the p.R337H mutation and has led to the hypothesis that p.R337H is a conditional mutant (DiGiammarino et al. Nat Struct Biol. 2002, 9:12-6; Giacomazzi J, et al. BMC Cancer 2013 Apr;13(1):187). Given the inter-familial variability in penetrance and tumor patterns described to date, some have suggested that surveillance recommendations for p.R337H carriers should be based on family cancer history (Palmero et al. Cancer Lett. 2008 Mar 8;261(1):21-5). Based on the available evidence, p.R337H is classified as a pathogenic mutation. -

Adrenocortical carcinoma, hereditary

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 28, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome-Nilou Lab	Apr 27, 2021	A 4-year-old girl with metastatic adrenocortical carcinoma in the right kidney & multiple gallstones. The father also has this type of cancer. -

Adrenocortical carcinoma, pediatric

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Breast neoplasm

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 25, 2022

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Genetics Program, Instituto Nacional de Cancer

Nov 01, 2021

- -

TP53-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Oct 01, 2024

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

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

Eigen

Benign

0.0026

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.78

T;T;.;.;.;T;T;T

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.96

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

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.4

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

MutationTaster

Benign

0.98

A;A;A;A;A;A

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.1

.;.;.;N;.;N;.;.

REVEL

Pathogenic

0.69

Sift

Benign

0.038

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

Sift4G

Benign

0.15

T;T;T;T;T;T;T;T

Polyphen

0.96

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

Vest4

0.71

MutPred

0.93

.;.;.;Loss of MoRF binding (P = 0.0485);.;Loss of MoRF binding (P = 0.0485);.;.;

MVP

0.96

MPC

0.41

ClinPred

0.79

GERP RS

3.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Varity_R

0.74

gMVP

0.57

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