1-45333168-A-T

Position:

• chr1-45333168-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000456914.7(MUTYH):​c.307T>A​(p.Trp103Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. W103C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MUTYH ENST00000456914.7 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.81

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, 13 uncertain in ENST00000456914.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 1-45333168-A-T is Pathogenic according to our data. Variant chr1-45333168-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333168-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.391T>A	p.Trp131Arg	missense_variant, splice_region_variant	5/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.307T>A	p.Trp103Arg	missense_variant, splice_region_variant	5/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.391T>A	p.Trp131Arg	missense_variant, splice_region_variant	5/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.307T>A	p.Trp103Arg	missense_variant, splice_region_variant	5/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251412 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135884

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: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 727248

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: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 131 of the MUTYH protein (p.Trp131Arg). This variant is present in population databases (rs730881832, gnomAD 0.0009%). This missense change has been observed in individual(s) with colon cancer and MUTYH-associated polyposis (PMID: 12853198, 19032956, 19394335, 19732775, 25820570, 26681312; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Trp117Arg. ClinVar contains an entry for this variant (Variation ID: 182688). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2021	Variant summary: MUTYH c.391T>A (p.Trp131Arg) results in a non-conservative amino acid change located in the HhH-GPD domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 3/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251412 control chromosomes (gnomAD). c.391T>A has been reported in the literature in individuals affected with MUTYH-Associated Polyposis (e.g. Sampson_2003, Jones_2009, Susswein_2016, Sutcliffe_2019). These data indicate that the variant is likely to be associated with disease. A functional study, Komine_2015, found the variant to be defective in base excision repair in a MUTY-deficient E. coli complementation assay. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 14, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 11, 2024	The p.W131R pathogenic mutation (also known as c.391T>A) is located in coding exon 5 of the MUTYH gene. This alteration results from a T to A substitution at nucleotide position 391. The tryptophan at codon 131 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in conjunction with the MUTYH p.Y179C pathogenic mutation in an individual with 152 colorectal polyps diagnosed at age 30 (Sampson JR et al. Lancet 2003 Jul; 362(9377):39-41; Vogt S et al. Gastroenterology 2009 Dec; 137(6):1976-85.e1-10). It was also detected in a patient diagnosed with colon cancer and colon polyps who underwent multi-gene panel testing (Susswein LR et al. Genet Med. 2016 Aug;18(8):823-32). Functional and structural assays demonstrated that this alteration is functionally defective and predicted to disrupt DNA-binding ability (David SS et al. Nature 2007 Jun;447(7147):941-50; Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). This alteration is also known as p.W117R in the published literature. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 09, 2023	This missense variant replaces tryptophan with arginine at codon 131 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). A functional study has shown that the variant protein is severely defective in a complementation assay conducted in E. coli (PMID: 25820570). This variant has been reported in two individuals with biallelic mutations in MUTYH and affected with MUTYH-associated polyposis, with one individual carrying the pathogenic co-variant c.536A>G (PMID: 12853198, 19032956, 19394335, 19732775, 30604180). This variant has also been reported in an individual affected with colon cancer and polyps (PMID 26681312). This variant has been identified in 1/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 08, 2020	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2024	Published functional studies demonstrate a damaging effect based on results of a complementation assay in E. coli (PMID: 25820570); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19822006, 26681312, 19732775, 12853198, 19032956, 19394335, 19725997, 17581577, 30604180, 25820570) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;.;.;.;.;D;.;.;.;T;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	.;.;.;.;.;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-12	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
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
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.
Vest4		0.96
MutPred		0.86		.;.;.;.;.;.;.;.;Gain of methylation at W131 (P = 0.0168);.;.;
MVP		1.0
MPC		0.74
ClinPred		1.0	D
GERP RS		5.5
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)		0.11		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: rs730881832; hg19: chr1-45798840;