1-45331241-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_001048174.2(MUTYH):c.1333G>A(p.Ala445Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,224 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A445S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14

Conservation

PhyloP100: 0.854

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45331240-G-T is described in Lovd as [Pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.1417G>A	p.Ala473Thr	missense_variant	14/16	ENST00000710952.2
MUTYH	NM_001048174.2 linkuse as main transcript	c.1333G>A	p.Ala445Thr	missense_variant	14/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.1417G>A	p.Ala473Thr	missense_variant	14/16		NM_001128425.2
MUTYH	ENST00000456914.7 linkuse as main transcript	c.1333G>A	p.Ala445Thr	missense_variant	14/16	1	NM_001048174.2	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251492

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

219

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

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:

0.000189

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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	Counsyl	Jan 25, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces alanine with threonine at codon 473 of the MUTYH protein. This variant is also known as c.1375G>A (p.Ala459Met) 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). Splice site prediction tools suggest that this variant may strengthen an alternative splice donor site. An RNA study using lymphoblastoid cell lines derived from a phenotypically normal subject has shown that this variant leads to the use of the alternative splice donor site (PMID: 31687339), creating a frameshift in the transcript. The clinical relevance of this observation is not known. A functional study has shown that this variant protein leads to similar base excision repair activity in comparison with the wild-type protein in a bacterial complementation assay (PMID: 25820570). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), multiple colorectal adenomas (PMID: 17949294), and breast cancer (PMID: 25186627). This variant has also been identified in 15/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	Invitae	Feb 01, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 473 of the MUTYH protein (p.Ala473Thr). This variant is present in population databases (rs192816572, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis (PMID: 14991577, 17949294; Invitae). 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.1375G>A (p.A459T). ClinVar contains an entry for this variant (Variation ID: 141614). 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 does not substantially affect MUTYH function (PMID: 25820570). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 15, 2019	Variant classified as Uncertain Significance - Favor Benign. The p.Ala473Thr var iant in MUTYH has been reported in the heterozygous state in one individual with colorectal cancer (Fleischmann 2004) and one individual who was tested for a Ly nch Syndrome-associated cancer or colorectal polyps (Yurgelun 2015). Another stu dy reported this variant in an unspecified number of individuals with adenomatou s polyposis (Olschwang 2007; variant reported as Ala459Thr). In vitro functional studies provide some evidence that the p.Ala473Thr variant may not impact prote in function (Komine 2015). However, these types of assays may not accurately rep resent biological function. This variant has also been reported in ClinVar (Vari ation ID 141614) and in 0.02% (14/129192) of European chromosomes by gnomAD (htt p://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis support that the p.Ala473Thr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary , while the clinical significance of the p.Ala473Thr variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BP 4, BS3_P. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2024	Variant summary: MUTYH c.1417G>A (p.Ala473Thr) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) and Adenine DNA glycosylase, C-terminal domain (IPR029119) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, several computational tools predict a significant impact on normal splicing: four predict the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence supporting computational predictions that this variant affects mRNA splicing, finding that the variant resulted in the utilization of a cryptic 5' donor site, leading to a frameshift (p.Ala473PhefsX38; Yamada_2019). The variant allele was found at a frequency of 5.2e-05 in 251686 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1417G>A has been reported in the literature in individuals affected with colorectal, breast, and cervical cancer, however without strong evidence for causality (e.g., Fleischmann_2004, Olschwang_2007, Tung_2014, Yurgelun_2015, Barreiro_2022). These reports therefore do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. One publication reports experimental evidence evaluating an impact on protein function, finding that the variant showed no damaging effect (e.g., Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 16134146, 14991577, 25820570, 26332594, 17949294, 25186627, 25980754, 34816434, 31687339). ClinVar contains an entry for this variant (Variation ID: 141614). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 14, 2023	In the published literature, this variant has been reported in individuals affected with colorectal cancer and/or polyps (PMID: 25980754 (2015), 17949294 (2007), 14991577 (2004)) or breast cancer (PMID: 25186627 (2015)). An experimental study suggested that this variant retained MUTYH functional activity in bacterial cells (PMID: 25820570 (2015)). However, another study detected aberrant splicing of MUTYH mRNA in a phenotypically normal individual carrying this variant (PMID: 31687339 (2019)). The frequency of this variant in the general population, 0.0002 (10/50820 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 deleterious or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on MUTYH mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2023	Published functional studies demonstrate normal base excision repair activity, but this variant may result in aberrant splicing (Komine et al., 2015; Yamada et al., 2019); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14991577, 25980754, 27498913, 17949294, 26332594, 16134146, 26269718, 19725997, 25186627, 31687339, 17031395, 25820570, 23108399, 15465463, 34816434) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2023	This missense variant replaces alanine with threonine at codon 473 of the MUTYH protein. This variant is also known as c.1375G>A (p.Ala459Met) 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). Splice site prediction tools suggest that this variant may strengthen an alternative splice donor site. An RNA study using lymphoblastoid cell lines derived from a phenotypically normal subject has shown that this variant leads to the use of the alternative splice donor site (PMID: 31687339), creating a frameshift in the transcript. The clinical relevance of this observation is not known. A functional study has shown that this variant protein leads to similar base excision repair activity in comparison with the wild-type protein in a bacterial complementation assay (PMID: 25820570). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), multiple colorectal adenomas (PMID: 17949294), and breast cancer (PMID: 25186627). This variant has also been identified in 15/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	Ambry Genetics	Feb 28, 2022	The c.1417G>A (p.A473T) alteration is located in exon 14 (coding exon 14) of the MUTYH gene. This alteration results from a G to A substitution at nucleotide position 1417, causing the alanine (A) at amino acid position 473 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Uncertain

0.060

Cadd

Benign

Dann

Benign

0.85

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.65

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.35

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

MetaSVM

Uncertain

0.51

MutationTaster

Benign

0.91

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

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.77

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

REVEL

Uncertain

0.59

Sift

Benign

0.14

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

Sift4G

Benign

0.10

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

Polyphen

0.043, 0.22, 0.14

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

Vest4

0.56

MVP

0.92

MPC

0.12

ClinPred

0.048

GERP RS

4.3

Varity_R

0.044

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.69

Position offset: 3

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