rs587782041

chr1-45333297-G-Achr1-45333297-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001048174.2(MUTYH):c.292C>T(p.Arg98Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R98Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.523

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.376C>T	p.Arg126Trp	missense_variant	4/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.292C>T	p.Arg98Trp	missense_variant	4/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.376C>T	p.Arg126Trp	missense_variant	4/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.292C>T	p.Arg98Trp	missense_variant	4/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251356 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135848

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: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461878 Hom.: 1 Cov.: 35 AF XY: 0.0000316 AC XY: 23 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 126 of the MUTYH protein (p.Arg126Trp). This variant is present in population databases (rs587782041, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 17949294). ClinVar contains an entry for this variant (Variation ID: 141830). 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 disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 07, 2023	This missense variant replaces arginine with tryptophan at codon 126 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant (also known as p.Arg112Trp in the literature) has been reported in an individual affected with multiple colorectal adenomas (PMID: 17949294). This variant has also been identified in 16/282734 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2021	This missense variant replaces arginine with tryptophan at codon 126 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant (also known as p.Arg112Trp in the literature) has been reported in an individual affected with multiple colorectal adenomas (PMID: 17949294). This variant has also been identified in 16/282734 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	Feb 20, 2024	The p.R126W variant (also known as c.376C>T), located in coding exon 4 of the MUTYH gene, results from a C to T substitution at nucleotide position 376. The arginine at codon 126 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected in a cohort of 453 individuals diagnosed with adenomatous polyposis (Olschwang S et al. Genet Test, 2007;11:315-20). Of note, this alteration is also designated as c.334C>T (p.R112W) in published literature. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 01, 2023

The frequency of this variant in the general population, 0.00029 (9/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with multiple colorectal adenomas (PMID: 17949294 (2007)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.
Vest4		0.72
MutPred		0.52		.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0238);.;.;
MVP		0.96
MPC		0.56
ClinPred		0.92	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782041; hg19: chr1-45798969;