rs533899702

chr1-45332785-C-T

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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• 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]

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: {Uncertain_significance=5, Likely_pathogenic=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.554G>A	p.Arg185Gln	missense_variant	7/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.470G>A	p.Arg157Gln	missense_variant	7/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.554G>A	p.Arg185Gln	missense_variant	7/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.470G>A	p.Arg157Gln	missense_variant	7/16	1	NM_001048174.2	A1

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 04, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2021	Variant summary: MUTYH c.554G>A (p.Arg185Gln) results in a conservative amino acid change located in the HhH (helix hairpin helix)-GPD domain (IPR003265) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251444 control chromosomes. In our ascertainment, c.554G>A has been reported in the literature as 1. a biallelic compound heterozygous genotype in a APC mutation negative patient with 50 polyps and no personal history of colorectal cancer, but a family history of colorectal cancer (Russel_2006), 2. as an uninformative genotype (i.e., single variant) in a 59 year old male with gall bladder tumor and a family history of one biliary tract cancer in first or second degree relatives (Terashima_2019), 3. with an uninformative genotype but a classification of Pathogenic in a single case within a cohort of unselected Japanese CRC patients and in a population control within the same study (Fujita_2020). These data do not allow firm conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a functionally defective base excision repair (BER) activity by a MutY-deficient Ecoli complementation assay (Komine_2015). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance citing overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2023	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. -

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
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
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;