rs1060501346

Positions:

chr1-45332457-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001048174.2(MUTYH):c.638G>A(p.Arg213Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,461,764 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R213W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.49

Variant links:

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 links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 7 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 chr1-45332458-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 1-45332457-C-T is Pathogenic according to our data. Variant chr1-45332457-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332457-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.638G>A	p.Arg213Gln	missense_variant	9/16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.638G>A	p.Arg213Gln	missense_variant	9/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1226G>A		non_coding_transcript_exon_variant	13/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

250422

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727180

show subpopulations

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:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 241 of the MUTYH protein (p.Arg241Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with polyposis or colon cancer and polyposis (100-500 polyps) and colorectal cancer (PMID: 19732775, 21520333; Invitae). ClinVar contains an entry for this variant (Variation ID: 406867). 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.Arg241 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14991577, 15673720, 24470512, 25820570, 27194394; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 12, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 08, 2024	The p.R241Q variant (also known as c.722G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 722. The arginine at codon 241 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in conjunction with a pathogenic MUTYH mutation in an individual diagnosed with colorectal cancer and polyposis (45y, 100-550 colorectal polyps), breast cancer (60y, 68y), spinalioma (68y), as well as a benign skin tumor, from a cohort of 276 index patients with adenomatous polyposis (Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10). This alteration has also been reported in 1 of 257 patients with MUTYH-associated polyposis (MAP) (Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6). 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 majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 31, 2022	This missense variant replaces arginine with glutamine at codon 241 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). To our knowledge, functional studies have not been reported for this variant, however, studies have shown that a different missense substitution at the same codon (p.Arg241Trp, also known as p.Arg227Trp in the literature) affects DNA binding and glycosylase activity of the MUTYH protein (PMID: 15673720, 25820570). The variant c.722G>A has been reported with a pathogenic variant (p.Gly396Asp) in MUTYH in an individual with polyposis (100-500 polyps), colorectal cancer, breast cancer, and spinalioma (PMID: 19732775). While it is unknown if these two variants are on the same or opposite chromosomes, this observation suggests the c.722G>A substitution may contribute to the cause of disease. Also, this variant has been observed in homozygosity in an individual with polyposis (PMID: 21520333). This variant has been identified in 7/250422 chromosomes 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

0.69

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

.;.;.;.;.;D;.;.;.;T;.;T

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

.;D;.;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

.;.;.;.;.;H;.;.;.;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.7

D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.95

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

Polyphen

1.0

.;.;.;.;.;D;D;.;D;.;.;.

Vest4

0.91

MutPred

0.88

.;.;.;.;.;.;.;.;Loss of helix (P = 0.028);.;.;.;

MVP

0.99

MPC

0.44

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over