rs200872702

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001048174.2(MUTYH):c.583A>G(p.Ile195Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I195I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:30

Conservation

PhyloP100: 1.15

Variant links:

Genes affected

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25944573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.583A>G	p.Ile195Val	missense_variant	8/16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 linkuse as main transcript	c.583A>G	p.Ile195Val	missense_variant	8/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 linkuse as main transcript	n.1171A>G		non_coding_transcript_exon_variant	12/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251390

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000211

AC:

309

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

152

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000251

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000353

Hom.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:30

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:9

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces isoleucine with valine at codon 223 of the MUTYH protein. Computational prediction 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 this variant causes a mild reduction in MUTYH activity in an enzymatic assay (PMID: 20848659), but could complement the functional deficiency of MutY-null bacteria (PMID: 25820570). This variant has been reported in individuals affected with adenomatous polyposis, colorectal adenomas, colon cancer, breast and/or ovarian cancer, thyroid cancer, or prostate cancer (PMID: 16287072, 12606733, 17949294, 21195604, 20618354, 27705013, 29368341, 30333958, 30680046, 31285513, Oliveira et al. 2021). All reported probands were heterozygous for this variant. This variant has also been identified in 57/282728 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in a healthy control (PMID: 32980694). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Molecular Oncology Laboratory, Hospital Clínico San Carlos	Jun 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Dec 29, 2021	The MUTYH c.667A>G (p.Ile223Val) missense change has a maximum subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-45798269-T-C). Both in silico tools and functional assays are not in agreement about the effect of this variant on protein function. A complementation assay evaluating functional deficiency in E.coli demonstrated that glycosylase repair activity was comparable to the wildtype (PMID: 25820570), whereas another study showed a moderate impairment of adenine DNA glycosylase activity (PMID: 20848659). This variant has been reported in individuals with adenomatous polyposis (PMID: 12606733, 16287072, 30680046 ), colorectal cancer (PMID: 21195604, 20618354, 31285513), colorectal adenomas (PMID: 17949294), prostate cancer (PMID: 29368341), breast and/or ovarian cancer (PMID: 30333958), and found to co-occur with a pathogenic BRCA2 mutation (p.Glu2846Glyfs*22) in an individual with breast cancer (PMID: 25186627). This variant has been reported in a 60 year old male with >100 colorectal polyps with colorectal cancer who was compound heterozygous for this variant and the pathogenic p.Tyr179Cys (PM3; PMID: 27705013). This variant is also known as p.Ile195Val and p.Ile209Val in the literature. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM3 -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 16, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 223 of the MUTYH protein (p.Ile223Val). This variant is present in population databases (rs200872702, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal polyposis, colon cancer, breast cancer, prostate cancer, and individuals undergoing hereditary cancer predisposition testing (PMID: 12606733, 16287072, 17949294, 20618354, 21195604, 23383274, 27705013, 29368341, 31159747, 31214250, 31285513). ClinVar contains an entry for this variant (Variation ID: 127847). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MUTYH function (PMID: 20848659, 25820570). 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. -

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2024	Published functional studies are inconclusive: partially reduced glycosylase activity, but mutation rates comparable to wild type (PMID: 20848659, 25820570); Observed in individuals with multiple polyps and/or colorectal cancer, including one who also carried a pathogenic MUTYH variant (phase unknown), and also in individuals with breast or pancreatic cancer (PMID: 16287072, 21195604, 27705013, 27829682, 30680046, 31285513, 31214250, 32255556); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as Ile195Val or Ile209Val; This variant is associated with the following publications: (PMID: 20848659, 17949294, 19725997, 21235684, 27153395, 30333958, 25820570, 21195604, 16287072, 25569433, 12606733, 23507534, 17161978, 20618354, 23383274, 27829682, 27705013, 29368341, 28492532, 17581577, 31159747, 31214250, 31277343, 30680046, 31285513, 32255556, 20725929, 26377631, 25186627, 28199314, 35264596, 34326862, 35534704, 35980532, 27443514, 32980694) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 25, 2023	The MUTYH c.667A>G (p.Ile223Val) variant has been reported in the published literature in individuals with classical or atypical adenomatous polyposis, colorectal cancer, prostate cancer, pancreatic cancer, or breast cancer (PMIDs: 12606733 (2003), 16287072 (2006), 17949294 (2007), 21195604 (2011), 23383274 (2013), 27829682 (2016), 27705013 (2016), 27153395 (2016), 29368341 (2018), and 32255556 (2020)). Experimental studies of this variants effects on MUTYH protein function have reported conflicting results (PMIDs: 20848659 (2010) and 25820570 (2015)). The frequency of this variant in the general population, 0.0019 (5/2670 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:6

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2023	This missense variant replaces isoleucine with valine at codon 223 of the MUTYH protein. Computational prediction 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 this variant causes a mild reduction in MUTYH activity in an enzymatic assay (PMID: 20848659), but could complement the functional deficiency of MutY-null bacteria (PMID: 25820570). This variant has been reported in individuals affected with adenomatous polyposis, colorectal adenomas, colon cancer, breast and/or ovarian cancer, thyroid cancer, or prostate cancer (PMID: 16287072, 12606733, 17949294, 21195604, 20618354, 27705013, 29368341, 30333958, 30680046, 31285513, Oliveira et al. 2021). All reported probands were heterozygous for this variant. This variant has also been identified in 57/282728 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in a healthy control (PMID: 32980694). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jun 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2024	The p.I223V variant (also known as c.667A>G), located in coding exon 8 of the MUTYH gene, results from an A to G substitution at nucleotide position 667. The isoleucine at codon 223 is replaced by valine, an amino acid with highly similar properties. This alteration has been described as heterozygous in individuals with polyposis but without second MUTYH or APC alterations (Sieber OM et al. N Engl J Med. 2003 Feb;348:791-9; Olschwang S et al. Genet. Test. 2007;11:315-20; Lorca V et al. Sci Rep. 2019 07;9:9814; Morak M et al. Clin Genet. 2010 Oct;78:353-63). A 60-year-old Italian patient with polyposis and colorectal cancer was found to have this variant in conjunction with the p.Tyr179Cys MUTYH founder mutation, although phase was not noted (Marabelli M et al. Genet Test Mol Biomarkers. 2016 12;20:777-785). The MUTYH p.I223V alteration has been reported to exhibit slightly lower glycosylation activity (66.9%) compared to wildtype (100%) and has been described as partially defective (Goto M et al. Hum Mutat. 2010 Nov;31:E1861-74; Komine K et al. Hum Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.I209V (c.625A>G) and p.I195V in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	Variant summary: MUTYH c.667A>G (p. Ile223Val) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 252250 control chromosomes, predominantly at a frequency of 0.00037 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.00037 vs 0.0046), allowing no conclusion about variant significance. In a comprehensive literature review spanning 16 years (2003-2019), c.667A>G has been widely reported in the literature in sequencing studies of individuals affected with breast cancer, APC-negative polyposis, attenuated polyposis, as a non-reportable incidental finding in settings of WES, in compound heterozygosity with another MUTYH variant in a colorectal cancer patient with an autosomal dominant family history, with a medium penetrance MUTYH variant in a colorectal cancer patient (e.g., Hilbers_2013, Sieber_2003, Russell_2006, Olschwang_2007, Morak_2010, Morak_2011, Jurgens_2015, Marabelli_2016, Tung_2015, Lorca_2019, Henn_2019, Yurgelun_2017, Maxwell_2016). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.8537_8538del, p. Glu2846Glyfs*22) in a patient with breast cancer, providing supporting evidence for a benign role (Tung_2015). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a moderate impairment of adenine DNA glycosylase activity (Goto_2010) which is contrasted by a normal activity in a functional complementation assay in E. coli (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26377631, 17161978, 17581577, 20848659, 29368341, 23383274, 25569433, 25820570, 31285513, 27705013, 27153395, 20618354, 21195604, 17949294, 20725929, 16287072, 12606733, 25186627, 28135145). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories (n = 21) classified the variant as uncertain significance. Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was evaluated to retain its classification as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2017	The p.Ile223Val variant in MUTYH has been reported in 4 individuals with adenoma tous polyposis as well as in 3 affected relatives from 1 family (Sieber 2003, Ru ssell 2006, Morak 2010, Morak 2011). However, no second MUTYH variant was detect ed in any of the affected individuals. This variant has been identified in 43/12 6744 of European chromosomes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org/; dbSNP rs200872702). In vitro functional studies are conflicting with one study suggesting partial impact on protein function and ano ther study suggesting no impact (Goto 2010, Komine 2015). However, these types o f assays may not accurately represent biological function. Additionally, computa tional prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance o f the p.Ile223Val variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 24, 2021	DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.667A>G, in exon 8 that results in an amino acid change, p.Ile223Val. This sequence change has been described in the gnomAD database with a low population frequency of 0.02% (dbSNP rs200872702). The p.Ile223Val change affects a highly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile223Val substitution. The c.667A>G (p.Ille223Val) sequence change has been reported in the heterozygous state in individuals affected with familial adenomatous polyposis, colorectal adenomas and colon cancer (PMIDs:16287072, 21195604, 20618354, 27705013, 27829682). Functional studies report contradictory results. In vitro studies showed that the protein with this variant had slightly decreased glycosylase activity; however, it had comparable activity in comparison to wild-type protein in a functional complementation assay in E. coli (PMIDs: 20848659, 25820570). Due to these contrasting evidences, the clinical significance of the p.Ile223Val change remains unknown at this time. -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MUTYH p.Ile223Val variant was identified in 3 of 878 proband chromosomes (frequency: 0.003) from individuals or families with colorectal adenomas, FAP, or classic polyposis and was not identified in 214 control chromosomes from healthy individuals (Oliver 2003, Olschwang 2007, Russell 2006). The variant was also identified in dbSNP (ID: rs200872702) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and nine other submitters), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 55 of 277080 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23992 chromosomes (freq: 0.00004), Other in 4 of 6462 chromosomes (freq: 0.0006), Latino in 4 of 34418 chromosomes (freq: 0.0001), European in 43 of 126640 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), South Asian in 2 of 30782 chromosomes (freq: 0.00007), while the variant was not observed in the East Asian, and Finnish populations. To understand the functional consequences of this variant, 47 MUTYH gene variants were generated via site-directed mutagenesis, expressed in MutY - disrupted Escherichia coli, and assessed for their ability to complement the functional deficiency in the E. coli by monitoring spontaneous mutation rates (Komine, 2015). The p.Ile223Val variant retained function but was only partially active in the glycosylase assay. In addition, Morak et al. describe evidence for digenic inheritance in hereditary colorectal cancer with mutations in the base excision repair genes. In a single case, a germline paternal mutation in OGG1, in combination with a maternal MUTYH p.Ile223Val mutation was identified in a female patient with advanced synchronous colon cancer and adenomas at the age of 36 years. This could point towards digenic inheritance for colorectal cancer (CRC) predisposition (Morak 2011), although this remains a single case. The p.Ile223 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a 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. -

Familial adenomatous polyposis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Clinical Genetics, Medical University of Lodz

Dec 11, 2024

- -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 25, 2024

- -

Diffuse midline glioma, H3 K27-altered

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

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

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.076

MetaRNN

Benign

0.26

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

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

0.93

.;.;.;.;.;L;.;.;.;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.76

N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.051

T;D;T;T;T;D;T;T;D;T;T;T

Sift4G

Benign

0.15

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

Polyphen

0.96, 0.95

.;.;.;.;.;D;P;.;D;.;.;.

Vest4

0.40

MVP

0.93

MPC

0.27

ClinPred

0.034

GERP RS

5.4

Varity_R

0.16

gMVP

0.39

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