rs1064793779

chr1-45332602-C-Gchr1-45332602-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001048174.2(MUTYH):c.578G>C(p.Gly193Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. G193E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.662G>C	p.Gly221Ala	missense_variant	8/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.578G>C	p.Gly193Ala	missense_variant	8/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.662G>C	p.Gly221Ala	missense_variant	8/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.578G>C	p.Gly193Ala	missense_variant	8/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

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	Apr 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 24, 2021	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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 419302). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 221 of the MUTYH protein (p.Gly221Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2015

This variant is denoted MUTYH c.662G>C at the cDNA level, p.Gly221Ala (G221A) at the protein level, and results in the change of a Glycine to an Alanine (GGG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Gly221Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. MUTYH Gly221Ala occurs at a position that is conserved across species and is not located in a known functional domain (Ruggieri 2013, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MUTYH Gly221Ala is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2022

The p.G221A variant (also known as c.662G>C), located in coding exon 8 of the MUTYH gene, results from a G to C substitution at nucleotide position 662. The glycine at codon 221 is replaced by alanine, an amino acid with similar properties. 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	0.10
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.078	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.36
MutPred		0.65		.;.;.;.;.;.;.;.;Loss of catalytic residue at A220 (P = 0.0799);.;.;.;
MVP		0.95
MPC		0.17
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.73
gMVP		0.55

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

Other links and lift over

dbSNP: rs1064793779; hg19: chr1-45798274;