Genetic Variant MUTYH:p.Ser227Ile (chr1-45332415-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001048174.2(MUTYH):c.680G>T(p.Ser227Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S227G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 55 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.680G>T	p.Ser227Ile	missense_variant	Exon 9 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.680G>T	p.Ser227Ile	missense_variant	Exon 9 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1268G>T		non_coding_transcript_exon_variant	Exon 13 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Feb 12, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S255I variant (also known as c.764G>T), located in coding exon 9 of the MUTYH gene, results from a G to T substitution at nucleotide position 764. The serine at codon 255 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is conserved. 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

0.27

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.28

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

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

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

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.55

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

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.4

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

PhyloP100

3.6

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.8

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

REVEL

Uncertain

0.35

Sift

Uncertain

0.019

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

Sift4G

Uncertain

0.057

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

Polyphen

0.30, 0.26, 0.30

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

Vest4

0.58

MutPred

0.44

.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0157);.;.;.;

MVP

0.88

MPC

0.34

ClinPred

0.94

GERP RS

3.0

PromoterAI

0.014

Neutral

(source)

Varity_R

0.53

gMVP

0.73

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over