rs769237459

chr1-45332279-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001048174.2(MUTYH):c.736C>T(p.Arg246Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,461,788 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. R246Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.71

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 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 chr1-45332278-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41764.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Likely_pathogenic=4, not_provided=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 1-45332279-G-A is Pathogenic according to our data. Variant chr1-45332279-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.820C>T	p.Arg274Trp	missense_variant	10/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.736C>T	p.Arg246Trp	missense_variant	10/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.820C>T	p.Arg274Trp	missense_variant	10/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.736C>T	p.Arg246Trp	missense_variant	10/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250086 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461788 Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces arginine with tryptophan at codon 274 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant was categorized as functionally deficient (PMID: 25820570). This variant has been reported as biallelic with another MUTYH allele in individuals affected with MUTYH-associated polyposis (PMID: 16134147, 19732775, 26511139) and as a single in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/250086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 24, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 274 of the MUTYH protein (p.Arg274Trp). This variant is present in population databases (rs769237459, gnomAD 0.003%). This missense change has been observed in individual(s) with MUTYH-associated polyposis (PMID: 16134147, 19032956, 19394335, 19732775; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449417). 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). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 18, 2018	The p.Arg274Trp variant in MUTYH has been reported in the compound heterozygous state at least 2 individuals with MUTYH-associated polyposis (MAP) who had a sec ond pathogenic variant in MUTYH (Aceto 2005, Aretz 2005, Vogt 2009). Additionall y, it segregated with disease in at least one affected family member (Aceto 2005 ). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 449417) and has been identified in 1/33562 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg274Trp variant may impact protein function (Komine 2 015); however, these types of assays may not accurately represent biological fun ction. Computational prediction tools and conservation analysis support that the p.Arg274Trp variant may impact the protein. In summary, although additional stu dies are required to fully establish its clinical significance, this variant mee ts criteria to be classified as likely pathogenic for autosomal recessive MAP. A CMG/AMP criteria applied: PM2, PM3, PP1, PP3, PS3_Supporting. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2022	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; Published functional studies demonstrate a damaging effect: defective function in a MutY-deficient E. coli complementation assay (Komine et al., 2015); This variant is associated with the following publications: (PMID: 19032956, 16134147, 28349240, 26976419, 23770606, 19394335, 16557584, 19725997, 26511139, 19732775, 34426522, Feng2021[Abstract], 25820570, 11092888, 11160897) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 06, 2024	The p.R274W variant (also known as c.820C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 820. The arginine at codon 274 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in the literature in a compound heterozygous state with another MUTYH mutation in multiple individuals with adenomatous polyposis and/or GI cancers (Aceto GM et al, J. Exp. Clin. Cancer Res. 2015 ; 34():131; Aceto G et al, Hum. Mutat. 2005 Oct; 26(4):394; Vogt S et al, Gastroenterology 2009 Dec; 137(6):1976-85.e1-10; Aretz S et al. Int. J. Cancer 2006 Aug;119(4):807-14). A functional analysis of this alteration using E. coli complementation, protein stability, and subcellular localization in mammalian cells indicated that this alteration was functionally defective (Komine K et al, Hum. Mutat. 2015 Jul; 36(7):704-11). Of note, this alteration is also designated as p.R260W (c.778C>T) in published literature. Another alteration at the same codon, p.R274Q (c.821G>A), has been detected in conjunction with different pathogenic MUTYH founder mutations in individuals with adenomatous polyposis; however, the phase (whether in cis or trans) is not confirmed (Ambry internal data). This amino acid position is well 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	Nov 22, 2021	This missense variant replaces arginine with tryptophan at codon 274 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant was categorized as functionally deficient (PMID: 25820570). This variant has been reported as biallelic with another MUTYH allele in individuals affected with MUTYH-associated polyposis (PMID: 16134147, 19732775, 26511139) and as a single in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/250086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D;D;D;D;D;.;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.72
MutPred		0.68		.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0143);.;.;.;
MVP		0.99
MPC		0.56
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.84
gMVP		0.78

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: rs769237459; hg19: chr1-45797951; COSMIC: COSV58343540; COSMIC: COSV58343540;