rs121908380

Variant names:

• chr1-45333449-G-A
• rs121908380
• NM_001048174.2:c.228C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_001293192.2(MUTYH):​c.-49C>T variant causes a 5 prime UTR premature start codon gain 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_001293192.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:27
• 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]

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 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: {Uncertain_significance=1, Likely_benign=11, Benign=9}. Variant chr1-45333449-G-A is described in Lovd as [Likely_benign].
• 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 rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.228C>T	p.Tyr76Tyr	synonymous_variant	Exon 3 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.228C>T	p.Tyr76Tyr	synonymous_variant	Exon 3 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.816C>T		non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000499896.1

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

GnomAD2 exomes AF: 0.00140 AC: 353 AN: 251480 AF XY: 0.00130

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 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 AC: 14 AN: 33480

Gnomad4 AMR exome AF: 0.00145 AC: 65 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000580 AC: 5 AN: 86258

Gnomad4 FIN exome AF: 0.00431 AC: 230 AN: 53414

Gnomad4 NFE exome AF: 0.00175 AC: 1949 AN: 1112006

Gnomad4 Remaining exome AF: 0.00129 AC: 78 AN: 60396

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 AC: 0.000433192 AN: 0.000433192

Gnomad4 AMR AF: 0.00268 AC: 0.00267764 AN: 0.00267764

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00480 AC: 0.00480407 AN: 0.00480407

Gnomad4 NFE AF: 0.00178 AC: 0.00177863 AN: 0.00177863

Gnomad4 OTH AF: 0.00142 AC: 0.0014218 AN: 0.0014218

Alfa AF: 0.000397 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:27

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:12

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH: BP4, BP7 -

Jun 06, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:6

Jul 28, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 18, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 06, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4, BP7 c.312C>T, located in exon 3 of the MUTYH gene, is predicted to result in no amino acid change, p.(Tyr104=)(BP7). This variant is found in 204/118170, , with a filter allele frequency of 0.15% at 99% confidence, and 1 homozygous individual was reported in the gnomAD v2.1.1 database (European non-Finnish non-cancer data set). The SpliceAI algorithm predicts no significant impact on splicing for the variant and its isoforms (BP4). To our knowledge, functional studies have not been reported for this variant. This variant has been identified in ClinVar (8x benign, 18x likely benign, 1x uncertain significance) and LOVD (7x uncertain significance, 5x likely benign) databases. Based on currently available information, the variant c.312C>T is classified as a likely benign variant according to ACMG guidelines. -

Nov 28, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:5

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Mar 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 2 Uncertain:1 Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
Mutation Taster		=98/2	polymorphism

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;