rs757503642

Positions:

• chr1-45332779-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.476A>G​(p.Gln159Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.55

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 helix (size 4) in uniprot entity MUTYH_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2614687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.560A>G	p.Gln187Arg	missense_variant	7/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.476A>G	p.Gln159Arg	missense_variant	7/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.560A>G	p.Gln187Arg	missense_variant	7/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.476A>G	p.Gln159Arg	missense_variant	7/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251426 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 18, 2023	This missense variant replaces glutamine with arginine at codon 187 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 1/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 17, 2022	The p.Q187R variant (also known as c.560A>G), located in coding exon 7 of the MUTYH gene, results from an A to G substitution at nucleotide position 560. The glutamine at codon 187 is replaced by arginine, an amino acid with some highly similar properties. This amino acid position is 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	curation	Sema4, Sema4	Jun 06, 2021	- -

Familial adenomatous polyposis 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 11, 2023	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. ClinVar contains an entry for this variant (Variation ID: 185772). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (rs757503642, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 187 of the MUTYH protein (p.Gln187Arg). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This missense variant replaces glutamine with arginine at codon 187 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 1/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2017

This variant is denoted MUTYH c.560A>G at the cDNA level, p.Gln187Arg (Q187R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Gln187Arg was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Gln187Arg occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MUTYH Gln187Arg is a pathogenic or benign variant. 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.? -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.67
DEOGEN2	Benign	0.097	.;.;.;.;.;T;.;.;.;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	-0.085	.;.;.;.;.;N;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.031, 0.026, 0.032	.;.;.;.;.;B;B;.;B;.;.;.
Vest4		0.64
MutPred		0.54		.;.;.;.;.;.;.;.;Loss of ubiquitination at K192 (P = 0.0432);.;.;.;
MVP		0.88
MPC		0.17
ClinPred		0.24	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs757503642; hg19: chr1-45798451;