rs587780749

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_001048174.2(MUTYH):c.652G>T(p.Val218Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V218A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 0.702

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 Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-45332443-C-A is Pathogenic according to our data. Variant chr1-45332443-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332443-C-A is described in Lovd as [Pathogenic]. Variant chr1-45332443-C-A is described in Lovd as [Likely_pathogenic]. Variant chr1-45332443-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.652G>T	p.Val218Phe	missense_variant	9/16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.652G>T	p.Val218Phe	missense_variant	9/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1240G>T		non_coding_transcript_exon_variant	13/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000559

AC:

AN:

250286

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000335

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000945

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 15, 2022	ACMG classification criteria: PS4 moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 09, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces valine with phenylalanine at codon 246 of the MUTYH protein. This variant is also known as c.694G>T (p.Val232Phe) based on an alternative transcript (NM_001048171). 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 reported this variant protein exhibited partially defective glycosylase and DNA binding activity (PMID: 15673720) but showed conflicting results in E. coli complementation assays, from defective to wild-type activity (PMID: 15673720, 25820570). This variant has been reported in individuals affected with multiple adenomas or polyposis (PMID: 12606733, 19793053, 20687945). At least one of these individuals carried a second pathogenic MUTYH variant in the compound heterozygous state (PMID: 12606733) while another individual carried a MUTYH variant of uncertain significance in trans (PMID: 20687945). This variant has also been reported in individuals affected with colorectal cancer, including one individual who carried this variant in the homozygous state (PMID: 19531215; ClinVar SCV000186631.8). In addition, this variant has been observed in individuals affected with gastrointestinal/neuroendocrine tumors (PMID: 26556299), bilateral breast cancer (PMID: 24733792), unilateral breast cancer (PMID: 33471991, 35264596), and head neck squamous cell carcinoma (PMID: 34598035). This variant has been identified in 14/250286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2023	Variant summary: MUTYH c.736G>T (p.Val246Phe) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the 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 5.6e-05 in 250286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.736G>T has been reported in the literature as p.Val232Phe or p.Val246Phe in a biallelic genotype in at-least three individuals affected with features of MUTYH-associated polyposis (example, Sieber_2003, Lopez-Villar_2010, Filpe_2009) and has also been reported as a presumed heterozygous monoallelic occurrence in settings of multigene panel testing (example, Kurian_2014, Guindalini_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 11% of normal DNA glycosylase activity (Bai_2005) while another study characterized this as "functionally retained" attributing the discrepancy to different E. coli backgrounds in the experimental system utilized (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 18534194, 15673720, 26377631, 19793053, 35264596, 25820570, 24733792, 20687945, 12606733). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n=2; LP, n=10). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 246 of the MUTYH protein (p.Val246Phe). This variant is present in population databases (rs587780749, gnomAD 0.04%). This missense change has been observed in individual(s) with MUTYH-associated polyposis (PMID: 12606733, 19793053, 20687945). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.694G>T, p.Val232Phe. ClinVar contains an entry for this variant (Variation ID: 135990). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15673720, 18534194). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 22, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 01, 2015	- -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 12, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 28, 2024	The missense variant NM_001128425.2(MUTYH):c.736G>T (p.Val246Phe) causes the same amino acid change as a previously established pathogenic variant. There is a small physicochemical difference between valine and phenylalanine, which is not likely to impact secondary protein structure as these residues share similar properties. 6 variants within 6 amino acid positions of the variant p.Val246Phe have been shown to be pathogenic, while none have been shown to be benign. For these reasons, this variant has been classified as Likely Pathogenic -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 04, 2024	The p.V246F variant (also known as c.736G>T), located in coding exon 9 of the MUTYH gene, results from a G to T substitution at nucleotide position 736. The valine at codon 246 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with adenomatous polyposis who also carried another MUTYH mutation, including one individual with both polyposis and colorectal cancer (Sieber OM et al. N. Engl. J. Med. 2003 Feb;348(9):791-9; Filipe B et al. Clin. Genet. 2009 Sep:76(3):242–55; Gómez-Fernández N et al. BMC Med. Genet., 2009 Jun;10:57; López-Villar I et al. BMC Cancer. 2010 Aug;10:408). Functional analyses of the mutated protein revealed reduced glycosylase and DNA binding activities compared to the wild type enzyme (Bai H et al. Nucleic Acids Res. 2005 Jan;33(2):597-604). Of note, this alteration is also designated as p.V232F in the published literature. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2023	This missense variant replaces valine with phenylalanine at codon 246 of the MUTYH protein. This variant is also known as c.694G>T (p.Val232Phe) based on an alternative transcript (NM_001048171). 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 reported this variant protein exhibited partially defective glycosylase and DNA binding activity (PMID: 15673720) but showed conflicting results in E. coli complementation assays, from defective to wild-type activity (PMID: 15673720, 25820570). This variant has been reported in individuals affected with multiple adenomas or polyposis (PMID: 12606733, 19793053, 20687945). At least one of these individuals carried a second pathogenic MUTYH variant in the compound heterozygous state (PMID: 12606733) while another individual carried a MUTYH variant of uncertain significance in trans (PMID: 20687945). This variant has also been reported in individuals affected with colorectal cancer, including one individual who carried this variant in the homozygous state (PMID: 19531215; ClinVar SCV000186631.8). In addition, this variant has been observed in individuals affected with gastrointestinal/neuroendocrine tumors (PMID: 26556299), bilateral breast cancer (PMID: 24733792), unilateral breast cancer (PMID: 33471991, 35264596), and head neck squamous cell carcinoma (PMID: 34598035). This variant has been identified in 14/250286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 26, 2022	The frequency of this variant in the general population, 0.00038 (13/34544 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with polyposis who also carry a second pathogenic MUTYH variant (PMIDs: 20687945 (2010), 19793053 (2009), 12606733 (2003)). It has also been reported in individuals affected with polyposis and without a second pathogenic MUTYH variant (PMID: 19531215 (2009)) as well as breast cancer (PMID: 24733792 (2014)). Functional studies have shown that this variant has reduced binding and glycosylase activity (PMID: 15673720 (2005)) while another study showed indirectly that the variant was able to limit spontaneous mutations in a manner comparable to the wild-type (PMID: 25820570 (2015)). Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2024	Published functional studies demonstrate a damaging effect: reduced glycosylase and DNA-binding activity as compared to wild type; however, ability to suppress mutation rates in MutY-deficient E. coli have been mixed (PMID: 15673720, 25820570); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26694661, 23605219, 19531215, 20687945, 19506731, 26556299, 19793053, 25820570, 15673720, 24733792, 12606733, 17161978, 18534194, 16042573, 23507534, 20725929, 19931546, 28152038, 35264596, 23108399, 11801590, 35980532, 34598035, 33471991, 35534704) -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 08, 2024

- -

Pilomatrixoma

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 25, 2019

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 12606733, 15673720, 25820570, 24733792, 28152038, 26556299; ClinVar: 135990] -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

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

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.62

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

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.81

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

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

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

REVEL

Uncertain

0.54

Sift

Benign

0.064

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

Sift4G

Uncertain

0.044

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

Polyphen

0.017, 0.055, 0.14

.;.;.;.;.;B;B;.;B;.;.;.

Vest4

0.72

MutPred

0.81

.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.09);.;.;.;

MVP

0.80

MPC

0.24

ClinPred

0.059

GERP RS

3.6

Varity_R

0.50

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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