rs1060501339

Positions:

• chr1-45333441-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001048174.2(MUTYH):​c.236A>G​(p.Glu79Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. E79K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.46

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 2 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, 17 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18391663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.320A>G	p.Glu107Gly	missense_variant	3/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.236A>G	p.Glu79Gly	missense_variant	3/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.320A>G	p.Glu107Gly	missense_variant	3/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.236A>G	p.Glu79Gly	missense_variant	3/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 06, 2023

ClinVar contains an entry for this variant (Variation ID: 406854). 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 tolerated. This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 107 of the MUTYH protein (p.Glu107Gly). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2023

The p.E107G variant (also known as c.320A>G), located in coding exon 3 of the MUTYH gene, results from an A to G substitution at nucleotide position 320. The glutamic acid at codon 107 is replaced by glycine, an amino acid with similar properties. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.092	.;.;.;.;.;T;.;.;.;T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.91	.;D;.;D;D;D;D;D;D;D;D;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.0	.;.;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N;N;D
REVEL	Benign	0.24
Sift	Benign	0.47	T;T;T;T;T;T;T;T;T;D;T;D
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.011, 0.014, 0.0080	.;.;.;.;.;B;B;.;B;.;.;.
Vest4		0.14
MutPred		0.46		.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0207);.;.;.;
MVP		0.91
MPC		0.14
ClinPred		0.16	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1060501339; hg19: chr1-45799113;