rs121908380

Positions:

• chr1-45333449-G-A
• chr1-45333449-G-C
• chr1-45333449-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_001048174.2(MUTYH):​c.228C>T​(p.Tyr76=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,614,190 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (6 hom.)
• Consequence: MUTYH NM_001048174.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:26
• Conservation: PhyloP100: -0.362

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-45333449-G-A is Benign according to our data. Variant chr1-45333449-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132760.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=8, Uncertain_significance=1}. Variant chr1-45333449-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.362 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.312C>T	p.Tyr104=	synonymous_variant	3/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.228C>T	p.Tyr76=	synonymous_variant	3/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.312C>T	p.Tyr104=	synonymous_variant	3/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.228C>T	p.Tyr76=	synonymous_variant	3/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00140 AC: 353 AN: 251480 Hom.: 0 AF XY: 0.00130 AC XY: 177 AN XY: 135914

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00160 AC: 2341 AN: 1461882 Hom.: 6 Cov.: 35 AF XY: 0.00153 AC XY: 1110 AN XY: 727240

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00431

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74488

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00127

EpiCase AF: 0.00158

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:26

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:12

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2016	Variant summary: The MUTYH c.312C>T (p.Tyr104Tyr) 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. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 161/124730 control chromosomes at a frequency of 0.0012908, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0055902). This variant has been reported in numerous patients with various types of cancer, however, without enough evidence suggesting pathogenicity. In one internal sample (91 y.o.), co-occurrence of this variant and BRIP1 c.484C>T (classified as likely pathogenic by LCA) was found, suggesting the variant of interest is unlikely to be pathogenic. 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	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MUTYH: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 26, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 14, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 22, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:5

Likely 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	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: ExAC: 0.5% Finnish chromosomes; ClinVar: 4 labs classify as LB/B -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2013	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2015	- -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 18, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 17, 2017	- -

Familial adenomatous polyposis 2 Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Dec 03, 2015	- -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MUTYH p.Tyr104= variant was identified in 6 of 8036 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer, breast cancer, or adenomatous polyposis and was not identified in 3332 control chromosomes from healthy individuals (Out 2012, Aretz 2006, Alhopuro 2005, McVeigh 2016, Niessen 2006, Olschwang 2007). The variant was also identified in dbSNP (ID: rs121908380) as “With Pathogenic, other allele”, ClinVar (classified as benign by Invitae, GeneDx, Color Genomics and 4 clinical laboratories; as likely benign by Ambry Genetics and 3 clinical laboratories), Clinvitae, and COGR database. The variant was not identified in Cosmic, or UMD-LSDB databases. The variant was identified in control databases in 417 of 277196 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 13 of 24020 chromosomes (freq: 0.001), Other in 16 of 6464 chromosomes (freq: 0.002), Latino in 50 of 34420 chromosomes (freq: 0.001), European in 213 of 126700 chromosomes (freq: 0.002), East Asian in 1 of 18870 chromosomes (freq: 0.0001), Finnish in 123 of 25788 chromosomes (freq: 0.01), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish populations. The p.Tyr104= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.8
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs121908380; hg19: chr1-45799121; COSMIC: COSV58343431; COSMIC: COSV58343431;