chr1-45331241-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP5

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 Conflicting classifications of pathogenicity (no stars). 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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:12

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:

ENSG00000288208 (HGNC:):

ENSG00000288208 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].

PP5

Variant 1-45331241-C-T is Pathogenic according to our data. Variant chr1-45331241-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141614.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=12, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.1333G>A	p.Ala445Thr	missense_variant	Exon 14 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.1333G>A	p.Ala445Thr	missense_variant	Exon 14 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1921G>A		non_coding_transcript_exon_variant	Exon 18 of 21			ENSP00000499896.1		A0A5F9ZGZ0

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:2Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 25, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	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; internal data). 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 (internal data). 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. -
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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' splicing 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). This finding was largely corroborated by RNA analysis performed at our partner laboratory. The variant allele was found at a frequency of 5.2e-05 in 251686 control chromosomes. 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). It has however, been observed in trans with other pathogenic alleles in at-least two individuals affected with features of MUTYH-Associated Polyposis at our laboratory (Internal data). These data indicate that the variant is likely to be associated with disease. At least one publication reports in-vitro experimental evidence evaluating an impact on protein function by E-coli base excision repair. These results showed no damaging effect of this variant (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 16134146, 34816434, 14991577, 25820570, 26332594, 17949294, 25186627, 31687339, 25980754). ClinVar contains an entry for this variant (Variation ID: 141614). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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	Baylor Genetics	Feb 07, 2024	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 28, 2024	The MUTYH c.1417G>A (p.Ala473Thr) variant has been reported in the published literature in individuals affected with colorectal cancer and/or polyps (PMIDs: 25980754 (2015), 17949294 (2007), 14991577 (2004)), and breast cancer (PMID: 25186627 (2015)). Experimental studies regarding the variant's impact on protein function report inconclusive findings as to whether or not this variant is damaging (PMIDs: 31687339 (2019), 25820570 (2015)). 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	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) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
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. -

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	Mar 18, 2024	The p.A473T variant (also known as c.1417G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1417. The alanine at codon 473 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in several patient cohorts including an early-onset colorectal cancer patient, an individual with greater than 5 colorectal adenomas, and an individual who underwent clinical genetic testing for Lynch syndrome; however, no other alterations in the MUTYH gene were detected in these cases, and p.A473T was classified as a variant of unknown significance (Fleischmann C et al. Int. J. Cancer. 2004 Apr;109:554-8; Olschwang S et al. Genet. Test. 2007;11:315-20; Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). Functional studies of this variant demonstrate that it has near-wild type function in an E. coli-based complementation assay; however, glycosylase assays have never been conducted on this variant (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.A459T in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, 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

DEOGEN2

Benign

0.17

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

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.79

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

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

MutationAssessor

Uncertain

2.2

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

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