rs150269172

Positions:

• chr1-45331209-G-A
• chr1-45331209-G-C

Variant summary

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

The NM_001048174.2(MUTYH):​c.1365C>T​(p.Thr455=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,192 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: MUTYH NM_001048174.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -1.72

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=-0.9).
• BP6: Variant 1-45331209-G-A is Benign according to our data. Variant chr1-45331209-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 182701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331209-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00109 (166/152308) while in subpopulation SAS AF= 0.0199 (96/4828). AF 95% confidence interval is 0.0167. There are 3 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1449C>T	p.Thr483=	synonymous_variant	14/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1365C>T	p.Thr455=	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.1449C>T	p.Thr483=	synonymous_variant	14/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1365C>T	p.Thr455=	synonymous_variant	14/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152190 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00293 AC: 737 AN: 251486 Hom.: 14 AF XY: 0.00380 AC XY: 516 AN XY: 135918

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00462

Gnomad SAS exome AF: 0.0204

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00127 AC: 1851 AN: 1461884 Hom.: 39 Cov.: 32 AF XY: 0.00181 AC XY: 1318 AN XY: 727240

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00202

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152308 Hom.: 3 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74482

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000582

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 27, 2016	Variant summary: The MUTYH c.1449C>T (p.Thr483Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 388/121394 control chromosomes (7 homozygotes), predominantly observed in the South Asian subpopulation at a frequency of 0.0199855 (330/16512). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0055902), suggesting this is a benign polymorphism found primarily in the populations of South Asian origin. For comparison, p.Tyr104Ter is the most common pathogenic South Asian variant and occurs only 14/121398 ExAC chromosomes. The variant was reported in affected individuals in the literature, without any evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 17, 2018	- -

Familial adenomatous polyposis 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 21, 2019	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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 24, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 29, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 05, 2018	- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MUTYH p.Thr483= variant was identified in 1 of 162 proband chromosomes (frequency: 0.006) from individuals or families with hereditary non-polyposis colorectal cancer (Morak 2011). The variant was identified dbSNP (rs150269172) as “with other allele” and ClinVar (classified as benign by Invitae, GeneDx, Color and 4 other submitters; and as likely benign by Ambry Genetics, Prevention Genetics and 2 other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 745 of 277,238 chromosomes (14 homozygous) at a frequency of 0.003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 625 of 30,782 chromosomes (freq: 0.02, increasing the likelihood this could be a low frequency benign variant), African in 18 of 24,036 chromosomes (freq: 0.0007), Other in 10 of 6468 chromosomes (freq: 0.002), Latino in 2 of 34,420 chromosomes (freq: 0.00006), European in 5 of 126,722 chromosomes (freq: 0.00004), and East Asian in 85 of 18,868 chromosomes (freq: 0.005), while it was not observed in the Ashkenazi Jewish and Finnish populations. The p.Thr483= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150269172; hg19: chr1-45796881;