chr1-45332795-G-C

Variant names:

• chr1-45332795-G-C
• rs747993448
• NM_001128425.2:c.544C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001128425.2(MUTYH):​c.544C>G​(p.Arg182Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R182P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 2.53
• Publications: 18 publications found

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]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 47 uncertain in NM_001128425.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332794-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 651962.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-45332795-G-C is Pathogenic according to our data. Variant chr1-45332795-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 940199.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.544C>G	p.Arg182Gly	missense_variant	Exon 7 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.460C>G	p.Arg154Gly	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	ENST00000710952.2	c.544C>G	p.Arg182Gly	missense_variant	Exon 7 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7	c.460C>G	p.Arg154Gly	missense_variant	Exon 7 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1048C>G		non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:1 Uncertain:2

Nov 03, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 07, 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 glycine, which is neutral and non-polar, at codon 182 of the MUTYH protein (p.Arg182Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with polyposis (PMID: 21777424). ClinVar contains an entry for this variant (Variation ID: 940199). 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. This variant disrupts the p.Arg182 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15366000, 16557584, 19032956, 19394335, 20618354). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Feb 24, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21777424, 15236166, 34704405]. This variant is expected to disrupt protein structure [Myriad internal data].

Hereditary cancer-predisposing syndrome Pathogenic:1

May 26, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glycine at codon 182 of the MUTYH protein. This variant is also known as c.502C>G (p.Arg168Gly) 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 reported for this variant. However, two other missense variants at this codon have been reported as loss-of-function in mutation suppressive activity and in vitro glycosylase activity assays (PMID: 20848659, 23322991). This variant has been reported in homozygosity in an individual affected with colorectal cancer or polyposis (PMID: 21777424). Two different missense variants at the same codon, p.Arg182Cys and p.Arg182His, are reported as disease-causing in ClinVar (variation ID: 182689, 187280). These two other missense variants have been reported in heterozygosity with a second pathogenic MUTYH variant in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 15366000, 16207212, 16557584, 16890597, 19394335, 20618354). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;D;.;.;.;D;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.0	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.0	.;.;.;.;.;H;.;.;.;.;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Vest4		0.98
ClinPred		1.0	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.89
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs747993448; hg19: chr1-45798467;