rs533899702

Variant names:

• chr1-45332785-C-T
• rs533899702
• NM_001048174.2:c.470G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001048174.2(MUTYH):​c.470G>A​(p.Arg157Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R157W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.16

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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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, 15 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332786-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419386.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=5}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.470G>A	p.Arg157Gln	missense_variant	Exon 7 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.470G>A	p.Arg157Gln	missense_variant	Exon 7 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1058G>A		non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251444 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461884 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74454

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:2

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 185 of the MUTYH protein (p.Arg185Gln). This variant is present in population databases (rs533899702, gnomAD 0.006%). This missense change has been observed in individual(s) with familial adenomatous polyposis or gallbladder cancer (PMID: 16287072, 31666926). ClinVar contains an entry for this variant (Variation ID: 481821). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 25820570). 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. -

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 185 of the MUTYH protein. This variant is also known as c.512G>A (p.Arg171Gln) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A complementation assay using E. Coli has shown that the variant protein leads to increased spontaneous mutations compared to wild type protein (PMID: 25820570). This variant has been reported in the compound heterozygous state in an individual affected with attenuated familial adenomatous polyposis (PMID: 16287072). This variant has also been reported in individuals affected with biliary tract cancer (PMID: 31666926) and colorectal cancer (PMID: 33309985). This variant has been identified in 2/251444 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

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R185Q variant (also known as c.554G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 554. The arginine at codon 185 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a compound heterozygous state in a 60-year-old Swiss female attenuated familial adenomatous polyposis (AFAP) patient and was not observed in 200 chromosomes from Swiss control samples (Russell AM et al. Int. J. Cancer. 2006 Apr;118:1937-40). This alteration was also observed in a Japanese population cohort of 2049 individuals who underwent whole-genome sequencing (Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230) and in a cohort of patients diagnosed with biliary tract carcinoma undergoing multigene panel testing for hereditary cancer risk (Terashima T et al. Oncotarget, 2019 Oct;10:5949-5957). Furthermore, this variant was present in 0/1005 Japanese pancreatic cancer patients and in 1/23705 controls (Mizukami K et al. EBioMedicine, 2020 Oct;60:103033) and was identified in 1/12501 unselected Japanese colorectal cancer patients and in 1/23695 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). Of note, this variant is also referred to as c.545G>A (p.Arg182Gln) and p.R171Q in the 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Mar 30, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 185 of the MUTYH protein. This variant is also known as c.512G>A (p.Arg171Gln) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A complementation assay using E. Coli has shown that the variant protein leads to increased spontaneous mutations compared to wild type protein (PMID: 25820570). This variant has been reported in the compound heterozygous state in an individual affected with attenuated familial adenomatous polyposis (PMID: 16287072). This variant has also been reported in individuals affected with biliary tract cancer (PMID: 31666926) and colorectal cancer (PMID: 33309985). This variant has been identified in 2/251444 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 specified Uncertain:1

Feb 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUTYH c.554G>A (p.Arg185Gln) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.554G>A has been reported in the presumed compound heterozygous state in the literature in a APC mutation-negative patient with 50 polyps and no personal history of colorectal cancer, but a family history of colorectal cancer (Russell_2006). These data do not allow firm conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however the c. nomenclature and p.nomenclature were in conflict and therefore the data could not be used for variant scoring (Komine_2015). The following publications have been ascertained in the context of this evaluation (PMID: 33309985, 25820570, 16287072, 31666926). ClinVar contains an entry for this variant (Variation ID: 481821). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Aug 01, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect: reduced protein levels compared to wildtype (Komine et al., 2015); Observed in individuals with colorectal cancer, biliary tract carcinoma, or pancreatic cancer (Poulsen et al., 2008; Terashima et al., 2019; Mizukami et al., 2020); Observed in an individual with attenuated polyposis and a second pathogenic variant in MUTYH (Russell et al., 2006); Also known as c.545G>A, p.(R171Q); This variant is associated with the following publications: (PMID: 29192238, 31666926, 33309985, 32980694, 25820570, 19506731, 16287072) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;.;.;.;.;T;.;.;.;T;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.3	.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.29	T;T;T;T;T;T;T;T;T;D;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.95, 0.97, 0.98	.;.;.;.;.;P;D;.;D;.;.;.
Vest4		0.85
MutPred		0.89		.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0525);.;.;.;
MVP		0.95
MPC		0.57
ClinPred		0.91	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.74

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: rs533899702; hg19: chr1-45798457;