rs538383136

Positions:

• chr1-45332656-C-A
• chr1-45332656-C-G
• chr1-45332656-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001048174.2(MUTYH):​c.524G>T​(p.Arg175Leu) 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. R175P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.705

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332656-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.608G>T	p.Arg203Leu	missense_variant	8/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.524G>T	p.Arg175Leu	missense_variant	8/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.608G>T	p.Arg203Leu	missense_variant	8/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.524G>T	p.Arg175Leu	missense_variant	8/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces arginine with leucine at codon 203 of the MUTYH protein (p.Arg203Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 406851). 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 disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;.;.;.;T;.;.;.;T;.;T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.3	.;.;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	0.95	D;D;D;D;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.026	D;D;D;D;D;D;D;D;D;D;T;T
Sift4G	Benign	0.086	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.92, 0.84, 0.92	.;.;.;.;.;P;P;.;P;.;.;.
Vest4		0.68
MutPred		0.46		.;.;.;.;.;.;.;.;Loss of helix (P = 0.028);.;.;.;
MVP		0.94
MPC		0.47
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.62
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs538383136; hg19: chr1-45798328;