rs587781864

Variant names:

• chr1-45332791-C-T
• rs587781864
• NM_001048174.2:c.464G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.464G>A​(p.Gly155Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,076 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G155S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.46

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 Pathogenic. Variant got 14 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 1-45332791-C-T is Pathogenic according to our data. Variant chr1-45332791-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.464G>A	p.Gly155Asp	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.464G>A	p.Gly155Asp	missense_variant	Exon 7 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1052G>A		non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461886 Hom.: 0 Cov.: 36 AF XY: 0.0000138 AC XY: 10 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: 0.000112

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

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: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:4

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 183 of the MUTYH protein (p.Gly183Asp). This variant is present in population databases (rs587781864, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis in the homozygous or compound heterozygous states (PMID: 20223003, 38201513; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 141595). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with aspartic acid at codon 183 of the MUTYH protein. This variant is also known as c.506G>A (p.Gly169Asp) 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two siblings who have an in-trans pathogenic MUTYH variant and are affected with familial polyposis (PMID: 20223003) as well as an individual carrying a second pathogenic variant in MUTYH and affected with colorectal polyposis (DOI: 10.33878/2073-7556-2022-21-2-58-63 ). This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 04, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Aug 25, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.506G>A, p.Gly169Asp; This variant is associated with the following publications: (PMID: 20223003) -

Sep 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.548G>A (p.Gly183Asp) variant has been reported in the published literature in-trans with another pathogenic MUTYH variant in an individual with familial adenomatous polyposis (PMID: 20223003 (2006)). In addition, this variant has been reported in-trans with a second MUTYH variant in individuals with a personal and family history of MUTYH-associated polyposis (personal communication with Ambry Genetics related to ClinVar ID: 141595). The frequency of this variant in the general population, 0.000004 (1/251458 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Apr 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with aspartic acid at codon 183 of the MUTYH protein. This variant is also known as c.506G>A (p.Gly169Asp) 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two siblings who have an in-trans pathogenic MUTYH variant and are affected with familial polyposis (PMID: 20223003) as well as an individual carrying a second pathogenic variant in MUTYH and affected with colorectal polyposis (DOI: 10.33878/2073-7556-2022-21-2-58-63 ). This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 19, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G183D pathogenic mutation (also known as c.548G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 548. The glycine at codon 183 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in conjunction with another pathogenic MUTYH mutation in two brothers with polyposis (Skrzypczak M et al. Hered. Cancer Clin. Pract. 2006;4:43-7). In addition, this alteration has been identified in several individuals with a second known MUTYH mutation in trans and a personal and family history consistent with MUTYH-associated polyposis (MAP) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Colon cancer Pathogenic:1

Apr 26, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MUTYH p.Gly183Asp variant was identified in 1 of 180 proband chromosomes (frequency: 0.006) from Polish individuals or families with FAP (Skrzypczak 2006). In this study the proband was affected with familial polyposis but negative for an APC pathogenic variant, and the variant co-occurred in trans with a pathogenic MUTYH variant (494A>G, Y165C). Similar observations have been made by our laboratory in two individuals both with MUTYH-related disease and with co-occurring MUTYH pathogenic variants (c.536A>G, p.Tyr179Cys and c.1187G>A, p.Gly396Asp) however phase was not determined. In discussion with additional clinical laboratories we identified multiple affected patients with this variant and a co-occurring pathogenic MUTYH variant, although phase was generally undetermined there was one case where phase was determined to be trans. The variant was also identified in dbSNP (ID: rs587781864) as “With Likely pathogenic” allele, and in ClinVar (classified with conflicting interpretations of pathogenicity; submitters: pathogenic by Ambry Genetics, likely pathogenic by GeneDx and Color, and uncertain significance by Invitae). The variant was identified in control databases in 1 of 246272 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), observed in the following population: Finnish in 1 of 22300 chromosomes (freq: 0.00005) while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian and South Asian populations. The p.Gly183 residue is conserved in mammals and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) predict that the variant will impact the function of the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;.;.;.;.;D;.;.;.;T;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;.;D;D;D;D;D;D;D;D;D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.0092	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.87
MutPred		0.82		.;.;.;.;.;.;.;.;Loss of methylation at R182 (P = 0.0471);.;.;.;
MVP		0.95
MPC		0.62
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94

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: rs587781864; hg19: chr1-45798463;