1-45331227-C-G

Position:

• chr1-45331227-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000456914.7(MUTYH):​c.1347G>C​(p.Thr449=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,614,218 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T449T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (61 hom.)
• Consequence: MUTYH ENST00000456914.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:22
• Conservation: PhyloP100: 0.762

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-45331227-C-G is Benign according to our data. Variant chr1-45331227-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 183787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331227-C-G is described in Lovd as [Likely_benign]. Variant chr1-45331227-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.762 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00528 (804/152328) while in subpopulation EAS AF= 0.0314 (163/5192). AF 95% confidence interval is 0.0275. There are 12 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1431G>C	p.Thr477=	synonymous_variant	14/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1347G>C	p.Thr449=	synonymous_variant	14/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1431G>C	p.Thr477=	synonymous_variant	14/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1347G>C	p.Thr449=	synonymous_variant	14/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 801 AN: 152210 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00987

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0313

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00461 AC: 1159 AN: 251482 Hom.: 13 AF XY: 0.00433 AC XY: 589 AN XY: 135914

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0249

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.00869

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00264 AC: 3853 AN: 1461890 Hom.: 61 Cov.: 32 AF XY: 0.00266 AC XY: 1935 AN XY: 727244

Gnomad4 AFR exome AF: 0.00959

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00451

Gnomad4 EAS exome AF: 0.0398

Gnomad4 SAS exome AF: 0.00358

Gnomad4 FIN exome AF: 0.00839

Gnomad4 NFE exome AF: 0.000682

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152328 Hom.: 12 Cov.: 33 AF XY: 0.00597 AC XY: 445 AN XY: 74496

Gnomad4 AFR AF: 0.00977

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0314

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.00678

Gnomad4 NFE AF: 0.000999

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00560

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 31, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, high frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2014	- -

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27829682, 27884173, 16774938, 20981092) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MUTYH: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 28, 2023	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 17, 2014	This alteration is classified as 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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 11, 2023	- -

Familial adenomatous polyposis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 09, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Thr477Thr (c.1431G>C ) variant (alias 1389G>C) has been previously reported in the literature in 14/332 proband chromosomes (frequency 0.048) in individuals affected with either adenomatous polyposis, gastric cancer or colorectal cancer, however controls were not included in these studies (Peterlongo 2006, Tao 2004, Yanaru-Fujisawa 2008). This variant has also been identified in the HGMD and LOVD databases, however it is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, and has been reported in dbSNP (ID#:rs74318065), by the 1000 genomes project (frequency 0.016), and ESP project (frequency 0.004). However, there is some conflicting information in the literature. In one study the variant c.1431G > C was found to be in complete linkage disequilibrium with two other MUTYH variants, –280G > A and c.36+11C>T (alias IVS1+11C>T). A statistically significant association was demonstrated between one of these variants, c.36+11C>T and increased CRC risk (Tao 2008). This indicates that individuals with the MUTYH – 280A/c.36+11T/c.1431C genotypes may be susceptible to CRC (Tao 2008). However, replication in additional cohorts and additional functional evidence would be required to validate this finding. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as a variant of unknown significance (VUS). -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.40
DANN	Benign	0.62

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: rs74318065; hg19: chr1-45796899; COSMIC: COSV58344222; COSMIC: COSV58344222;