rs147480076

chr1-45329389-G-Achr1-45329389-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001048174.2(MUTYH):c.1483C>T(p.Arg495Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000836 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign 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. R495H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 0.107

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03355658).
• BP6: Variant 1-45329389-G-A is Benign according to our data. Variant chr1-45329389-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185573.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2}. Variant chr1-45329389-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.1567C>T	p.Arg523Cys	missense_variant	16/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.1483C>T	p.Arg495Cys	missense_variant	16/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.1567C>T	p.Arg523Cys	missense_variant	16/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.1483C>T	p.Arg495Cys	missense_variant	16/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251480 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000759 AC: 111 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000894 AC XY: 65 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152164 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2022	The MUTYH c.1567C>T; p.Arg523Cys variant (rs147480076) is described in the literature in cohorts of individuals affected with polyposis and/or colorectal cancer, but the pathogenicity in both studies have not been ascertained (Ricci 2017, Yurgelun 2017). It is reported in ClinVar (Variation ID: 185573), and is observed in the general population at an overall frequency of 0.01% (25/282876 alleles) in the Genome Aggregation Database. The arginine at codon 523 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.166). Given the lack of clinical and functional data, the significance of the p.Arg523Cys variant is uncertain at this time. REFERENCES Ricci et al. Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study. J Hum Genet. 2017 Feb;62(2):309-315. PMID: 27829682. Yurgelun et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. PMID: 28135145. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 08, 2023	In the published literature, this variant has been reported in individuals suspected MUTYH-associated polyposis (PMID: 27829682 (2016)), breast cancer (PMID: 34371384 (2021)), or colorectal cancer (PMIDs: 34347074 (2022), 28135145 (2017)). The frequency of this variant in the general population, 0.00024 (6/25122 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 17, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 29, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 06, 2021	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2023	Variant summary: MUTYH c.1567C>T (p.Arg523Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (9.1e-05 vs 0.0046), allowing no conclusion about variant significance. c.1567C>T has been reported in the literature in sequencing studies of individuals with a suspected diagnosis of MUTYH-associated Polyposis and among patients with colorectal cancer (example, Ricci_2017, Yurgelun_2017, Biscaglia_2022). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Co-occurrence with other pathogenic variant(s) have been reported (CHEK2 c.470T>C , p.ile157Thr), providing supporting evidence for a benign role (Biscaglia_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27829682, 28135145, 34347074, 36243179). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=7) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial adenomatous polyposis 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 523 of the MUTYH protein (p.Arg523Cys). This variant is present in population databases (rs147480076, gnomAD 0.02%). This missense change has been observed in individual(s) with colon polyposis, colorectal cancer, breast cancer, ovarian cancer and/or pancreatic cancer (PMID: 27829682, 34347074, 34371384). This variant is also known as c.1525C>T (p.Arg509Cys). ClinVar contains an entry for this variant (Variation ID: 185573). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

MUTYH-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

The MUTYH c.1567C>T variant is predicted to result in the amino acid substitution p.Arg523Cys. This variant has been reported in an individual with MUTYH-associated polyposis and interpreted as uncertain significance (Table 1, Ricci et al. 2017. PubMed ID: 27829682). This variant is reported in 0.024% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185573/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	16
Dann	Benign	0.92
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.067
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.048	D
Vest4		0.087
MVP		0.20
ClinPred		0.043	T
GERP RS		0.70

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: rs147480076; hg19: chr1-45795061;