rs946755892

chr1-45333520-C-Achr1-45333520-C-G

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.157G>T(p.Val53Phe) 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. 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. V53L) 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:3
• Conservation: PhyloP100: -0.307

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122253895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.241G>T	p.Val81Phe	missense_variant	3/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.157G>T	p.Val53Phe	missense_variant	3/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.241G>T	p.Val81Phe	missense_variant	3/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.157G>T	p.Val53Phe	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 24, 2021	The p.V81F variant (also known as c.241G>T), located in coding exon 3 of the MUTYH gene, results from a G to T substitution at nucleotide position 241. The valine at codon 81 is replaced by phenylalanine, an amino acid with highly similar properties. This variant, designated as 199GT, was reported in an individual with 40-50 tubulovillous adenomas who was reported to be compound heterozygous for MYH-associated polyposis (MAP) (Di Gregorio C et al. Gastroenterology, 2006 Aug;131:439-44). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 30, 2019	- -

Familial adenomatous polyposis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 28, 2022

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 464708). This variant is also known as 199GT. This missense change has been observed in individual(s) with Tubulovillous adenoma (PMID: 16890597). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 81 of the MUTYH protein (p.Val81Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	12
Dann	Uncertain	0.98
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.28	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.55	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.068	T;T;T;T;T;T;D;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.0090, 0.016	.;.;.;.;.;B;B;.;B;.;.;.
Vest4		0.49
MutPred		0.39		.;.;.;.;.;.;.;.;Gain of helix (P = 0.132);.;.;.;
MVP		0.55
MPC		0.15
ClinPred		0.27	T
GERP RS		2.7
Varity_R		0.060
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs946755892; hg19: chr1-45799192;