chr1-45330557-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_001128425.2(MUTYH):c.1477G>T(p.Val493Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000435 in 1,608,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. V493I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

MUTYH
NM_001128425.2 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 3.53

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

familial adenomatous polyposis 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
colorectal cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 1-45330557-C-A is Pathogenic according to our data. Variant chr1-45330557-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2 link	c.1477G>T	p.Val493Phe	missense_variant, splice_region_variant	Exon 15 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 link	c.1393G>T	p.Val465Phe	missense_variant, splice_region_variant	Exon 15 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUTYH	ENST00000710952.2 link	c.1477G>T	p.Val493Phe	missense_variant, splice_region_variant	Exon 15 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7 link	c.1393G>T	p.Val465Phe	missense_variant, splice_region_variant	Exon 15 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1 link	n.1981G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 19 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000417

AC:

AN:

239690

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000929

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000453

AC:

AN:

1455982

Hom.:

Cov.:

AF XY:

0.0000456

AC XY:

AN XY:

723686

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33332

American (AMR)

AF:

0.00

AC:

AN:

44036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25998

East Asian (EAS)

AF:

0.00

AC:

AN:

39524

South Asian (SAS)

AF:

0.00

AC:

AN:

84998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000568

AC:

AN:

1109072

Other (OTH)

AF:

0.0000333

AC:

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000612

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:7

Aug 21, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 22, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Val493Phe variant (also known as p.Val479Phe in the literature) in MUTYH has been reported in 1 compound heterozygous individual with MUTYH-associated attenuated familial adenomatous polyposis (FAP; Aretz 2006), 1 compound heterozygous individual with colorectal adenomas (Reggoug 2009), 1 homozygous individual with sporadic colorectal cancer (CRC; Kury 2007), and 1 heterozygous individual with CRC with no second allele specified (Kury 2007). This variant has also been reported in ClinVar (Variation ID 219953). This variant has been identified in 3/15010 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587782228). This frequency is low enough to be consistent with the frequency of MUTYH-related attenuated FAP in the general population. In vitro functional studies provide some evidence that the p.Val493Phe variant may impact protein function (Grandval 2015, Komine 2015). Computational prediction tools and conservation analysis suggest that the p.Val493Phe variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Val493Phe variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PP3 -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 493 of the MUTYH protein (p.Val493Phe). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587782228, gnomAD 0.002%). This missense change has been observed in individuals with polyposis or colorectal cancer and/or small cell lung cancer (PMID: 16557584, 17931073, 17949294, 19806110, 20618354, 23729658, 33504652). This variant is also known as c.1435G>T (p.Val479Phe). ClinVar contains an entry for this variant (Variation ID: 219953). 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 disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 25820570). Studies have shown that this missense change results in skipping of exon 15 skipping, but is expected to preserve the integrity of the reading-frame (internal data). For these reasons, this variant has been classified as Pathogenic. -

Sep 11, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with phenylalanine at codon 493 in the nudix hydrolase domain 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). A functional study has shown the mutant protein to be partially defective in a complementation assay in a MutY-deficient E.coli strain (PMID: 25820570). This variant has been reported in homozygous or compound heterozygous state with other pathogenic variant in individuals affected with multiple colorectal adenomas (PMID: 16557584, 17949294). It has also been reported in a heterozygous individual affected with colorectal cancer (PMID: 17931073). This variant has been identified in 4/271092 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Oct 16, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.1477G>T affects a conserved nucleotide located at the first position of exon 15, resulting in amino acid change from Val to Phe. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not significantly affect normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. Grandval_2015 predicted that this variant leads to major loss of exon 5 and an inframe deletion (p.Val479_Met492del) based on RT-PCR product sequencing (data not shown). This variant has been reported in homozygous and compound heterozygous state in patients with atypical polyposis, colorectal adenomas, MUTYH associated polyposis. Heterozygous variant was found in 3/87104 control chromosomes at a frequency of 0.0000344 and one patient with sporadic colorectal cancer. One functional study in E.coli showed that protein with this variant partially lost the normal function in suppressing spontaneous mutations (Komine_2015). However, its function in human cells is still not clear. Taken together, this variant was classified as likely pathogenic. -

May 04, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 06, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Feb 28, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MUTYH c.1477G>T (p.Val493Phe) variant has been reported in the published literature in individuals affected with colorectal polyposis, adenomas, and/or cancer (PMID: 16557584 (2006), 17931073 (2007), 17949294 (2007), 19806110 (2009), 20618354 (2010)). It has also been reported in individuals affected with renal clear cell carcinoma (PMID: 26689913 (2015)), breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)), and small cell lung cancer (PMID: 33504652 (2021)). In addition, it has been identified in reportedly healthy individuals (PMID: 17931073 (2007), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). Functional studies report this variant results in a MUTYH protein with partially defective function (PMID: 25820570 (2015)) and causes exon 15 skipping (PMID: 25368107 (2015)). The frequency of this variant in the general population, 0.000033 (4/123030 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 predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

May 06, 2021

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek 2016); Reported in the homozygous or compound heterozygous state in at least 3 individuals with multiple colorectal adenomas, with or without colorectal cancer (Aretz 2006, Buecher 2008, Reggoug 2009); Published functional studies demonstrate a damaging effect: partially defective base excision repair activity in a yeast-based complementation assay (Komine 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1435G>T, p.Val479Phe; This variant is associated with the following publications: (PMID: 18787472, 29684080, 22493355, 22538434, 27631816, 21279954, 25368107, 26689913, 25820570, 20618354, 19806110, 16557584, 17931073, 17949294) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

May 15, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1477G>T pathogenic mutation (also known as p.V493F) is located in coding exon 15 of the MUTYH gene. The valine at codon 493 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 15 and this nucleotide position is highly conserved in available vertebrate species. This alteration has been identified both in conjunction with a pathogenic MUTYH mutation and in the homozygous state in polyposis patients (Aretz S et al. Int. J. Cancer. 2006 Aug 15;119:807-14; Olschwang S et al. Genet. Test. 2007;11:315-20; Ambry internal data). In addition, this alteration was classified by a functional complementation assay as partially defective (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.V479F (c.1435G>T) in published literature. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. -

Dec 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with phenylalanine at codon 493 in the nudix hydrolase domain of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study has shown the mutant protein to be partially defective in a complementation assay in a MutY-deficient E.coli strain (PMID: 25820570). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with multiple colorectal adenomas (PMID: 16557584, 17949294). It has also been reported in a heterozygous individual affected with colorectal cancer (PMID: 17931073). This variant has been identified in 4/271092 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Pathogenic:1

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MUTYH-related disorder

Pathogenic:1

Jul 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MUTYH c.1477G>T variant is predicted to result in the amino acid substitution p.Val493Phe. This variant was reported in multiple individuals with MUTYH-associated polyposis, colorectal cancer, or small cell lung cancer (see for example Aretz et al 2006. PubMed ID: 16557584; Küry et al 2007. PubMed ID: 17931073; Olschwang et al 2007. PubMed ID: 17949294; Reggoug et al 2009. PubMed ID: 19806110; Morak et al 2010. PubMed ID: 20618354; Tlemsani et al 2021. PubMed ID: 33504652). A published functional study demonstrated the damaging effect of this variant (Komine K et al 2015. PubMed ID: 25820570). This variant is also known as c.1435G>T (p.Val479Phe). This variant is reported in 0.0033% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45796229-C-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.5

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

PhyloP100

3.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.5

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

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.50, 0.86, 0.33

.;.;.;.;.;.;P;P;.;.;B;.

Vest4

0.80

MutPred

0.83

.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.1201);.;

MVP

0.95

MPC

0.62

ClinPred

0.97

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.57

gMVP

0.72

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

Splicevardb

3.0

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.43

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over