rs1441591597

Positions:

chr1-45331208-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001048174.2(MUTYH):c.1366G>A(p.Ala456Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A456V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.57

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.1366G>A	p.Ala456Thr	missense_variant	14/16	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.1366G>A	p.Ala456Thr	missense_variant	14/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 linkuse as main transcript	n.1954G>A		non_coding_transcript_exon_variant	18/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251490

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces alanine with threonine at codon 484 of the MUTYH protein. This variant is also known as c.1408G>A (p.Ala470Thr) based on an alternative transcript, NM_001048171. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having hereditary cancer syndrome (PMID: 25318351) and in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 1/251490 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	Labcorp Genetics (formerly Invitae), Labcorp	Jun 29, 2023	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. 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. ClinVar contains an entry for this variant (Variation ID: 479993). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 484 of the MUTYH protein (p.Ala484Thr). -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 10, 2023	This missense variant replaces alanine with threonine at codon 484 of the MUTYH protein. This variant is also known as c.1408G>A (p.Ala470Thr) based on an alternative transcript, NM_001048171. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having hereditary cancer syndrome (PMID: 25318351) and in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 1/251490 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 20, 2024	The p.A484T variant (also known as c.1450G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1450. The alanine at codon 484 is replaced by threonine, an amino acid with similar properties. This alteration was detected on a 25-gene panel test in a woman diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33) and was also reported as a variant of unknown significance in a cohort of 105 patients undergoing multi-gene panel testing (Yorczyk A et al, Clin. Genet. 2015 Sep; 88(3):278-82). This amino acid position is 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

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

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.62

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

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.6

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

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.2

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

REVEL

Uncertain

0.48

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.013

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

Polyphen

0.70, 0.95, 0.92

.;.;.;.;.;.;P;P;.;.;P;.

Vest4

0.49

MutPred

0.53

.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at A484 (P = 0.0441);.;

MVP

0.92

MPC

0.36

ClinPred

0.86

GERP RS

5.4

Varity_R

0.20

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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