chr1-45331485-G-T

Position:

chr1-45331485-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting

The NM_001048174.2(MUTYH):c.1174C>A(p.Leu392Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000553 in 1,614,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. L392V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:10

Conservation

PhyloP100: 2.35

Variant links:

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]

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_001048174.2

BP4

Computational evidence support a benign effect (MetaRNN=0.03738302).

BP6

Variant 1-45331485-G-T is Benign according to our data. Variant chr1-45331485-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41752.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=4, Benign=4}. Variant chr1-45331485-G-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 2 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_001048174.2 link	c.1174C>A	p.Leu392Met	missense_variant	13/16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.1174C>A	p.Leu392Met	missense_variant	13/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1762C>A		non_coding_transcript_exon_variant	17/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000558

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000585

AC:

147

AN:

251166

Hom.:

AF XY:

0.000707

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000947

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000625

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000564

AC:

824

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000617

AC XY:

449

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00187

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000547

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000453

AC:

AN:

152384

Hom.:

Cov.:

AF XY:

0.000429

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000414

Hom.:

Bravo

AF:

0.000559

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 30, 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. -
Uncertain significance, no assertion criteria provided	research	Center of Medical Genetics and Primary Health Care	Apr 08, 2020	ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: A domain DNA_Glycosylase_C (R354-483Y aa) involved in Adenine DNA glycosylation. Hot-spot has 24 non-VUS coding variants (12 PATH and 12 BEN), pathogenicity = 50.0%, proximity score 3.836 > threshold 2.472. PP2 Pathogenic Supporting: 59 out of 97 non-VUS missense variants in gene MUTYH are PATH = 60.8% > threshold of 51.0%, and 191 out of 1,184 clinically reported variants in gene MUTYH are PATH = 16.1% > threshold of 12.0%. PP3 Pathogenic Supporting: 7 pathogenic predictions from DANN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and SIFT vs 4 benign predictions from DEOGEN2, EIGEN, PrimateAI and REVEL. PP4 Pathogenic Supporting: The variant was detected in two unrelated female patients diagnosed with bilateral breast cancer or breast and ovarian cancers both with strong family history of breast and ovarian cancer. BS3 Benign Strong: At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an assay evaluating base excision repair (BER) with a MutY-Deficient E Coli complementation assay (PMID: 25820570). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 25, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

not provided

Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2024	The MUTYH c.1258C>A (p.Leu420Met) variant has been reported in individuals with colorectal cancer (PMID: 27829682 (2016), 24470512 (2014), 21287799 (2010), 17949294 (2007), 16774938 (2006)), breast cancer (PMID: 32658311 (2021), 30564557 (2018), 29700634 (2018), 28202063 (2017), 25503501 (2015)), ovarian cancer (PMID: 33558524 (2021), 26689913 (2015)), pancreatic cancer (PMID: 20110747 (2009)), and gastric cancer (PMID: 32066632 (2021)). In a large-scale breast cancer association study, this variant was reported in individuals with breast cancer as well as reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). A functional study in bacteria showed this variant does not affect MUTYH DNA damage repair activity (PMID: 25820570 (2015)). The frequency of this variant in the general population, 0.0022 (23/10364 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. ClinVar contains an entry for this variant (URL: www.ncbi.nlm.nih.gov/clinvar, Variation ID: 41752). 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MUTYH: BS2 -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 30, 2016	The p.Leu420Met variant in MUTYH has been reported in 4 individuals with colorectal cancer (Peterlongo 2006 - variant reported as Leu406Met, Ricci 2016), one of whom carried a second intronic variant in MUTYH, although phase was not known. Functional studies in bacteria (E.coli) suggest that the p.Leu420Met variant may not impact protein function (Komine 2015). However, these types of assays may not accurately represent biological function. This variant has been identified in 16/16506 South Asian chromosomes (0.1%) by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144079536). This frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein although 1 mammal (Pika) has the variant amino acid (Met) at this position. In summary, while the clinical significance of the p.Leu420Met variant is uncertain, these data suggest that it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	Observed in the heterozygous state in individuals with colorectal and other cancers (Peterlongo 2006, Olschwang 2007, Smith 2009, Guarinos 2014, Ballinger 2016, Jalkh 2017, Ricci 2017, Scarpa 2017, Rizzolo 2018); Observed with an intronic MUTYH variant in an individual with suspected MUTYH-associated polyposis (MAP), phase unknown (Ricci 2017); Published functional studies demonstrate no damaging effect: spontaneous mutation rates similar to wild type in an E. coli-based complementation assay (Komine 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24470512, 25503501, 28873162, 30564557, 25820570, 29700634, 21777424, 22703879, 20110747, 16774938, 18515411, 27829682, 17949294, 26632267, 28199314, 26269718, 27498913, 28717660, 28202063, 21153778, 19725997, 28526081, 21287799, 30374176, 26689913, 26580448) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Familial adenomatous polyposis 2

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 18, 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. 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. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Aug 01, 2016	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 36 year old with a history of 2 colon polyps and a family history of colon cancer. -
Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	May 17, 2018	The MUTYH variant designated as NM_001128425.1:c.1258C>A (p.Leu420Met, historically known as p.Leu417Met) was previously classified as a variant of uncertain significance and is now classified as likely benign. This variant has been reported in several population databases. It is present in approximately 1 in 900 individuals with European ancestry. This population frequency is not consistent with the frequency of pathogenic mutations in MUTYH. This variant is a missense variant and pathogenic variants in MUTYH are most frequently truncating variants. This variant has been classified as likely benign and benign by other laboratories (ClinVar Variation ID: 41752). Together, this information is consistent with a likely benign variant in MUTYH. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MUTYH function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 01, 2021	Variant summary: MUTYH c.1258C>A (p.Leu420Met) results in a conservative amino acid change located in the NUDIX hydrolase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 251380 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.00059 vs 0.0046), allowing no conclusion about variant significance. c.1258C>A has been reported in the literature in sequencing studies among individuals affected with MUTYH-associated Polyposis, a variety of other cancer types and in unaffected controls (example, Cabanillas_2017, Cheng_2017, Guarinos_2014, Jalkh_2017, Johnston_2012, Maxwell_2015, Olschwang_2007, Peterlongo_2006, Ricci_2016, Rosner_2010, Smith_2009, Zhang_2015, Singal_2017, Ackay_2021, Rizzolo_2018, Tsai_2019). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an assay evaluating base excision repair (BER) with a MutY-Deficient E Coli complementation assay (Komine_2015). Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance, n=9; benign/likely benign, n=4). Some submitters cite overlapping literature utilized in the context of our evaluation. Our laboratory, among others previously re-classified this variant from uncertain significance to likely benign. Its latest re-evaluation spanning a comprehensive review of published evidence still does not point to a concrete actionable outcome and the overall directionality of evidence seems to support a benign outcome. Based on all the evidence outlined above, the variant was re-classified as benign. -

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.Leu420Met variant was identified in 2 of 1084 proband chromosomes (frequency: 0.002) from individuals or families with MMR negative colon cancer or MUTYH-associated polyposis (Peterlongo 2006, Guarinos 2014). The variant was also present in 1 of 1096 chromosomes (frequency: 0.001) from individuals with atherosclerosis phenotypes with who underwent secondary variant detection (Johnston 2012). In a functional E. coli-based complementation assay, the variant retained functional expression, showing spontaneous mutation rates similar to wild type (Komine 2015). The variant was identified in dbSNP (ID: rs144079536) "With Uncertain significance, other allele", and ClinVar (classified with conflicting interpretations of pathogenicity: benign by Ambry Genetics and Color; likley benign by Invitae and two other laboratories; and uncertain significance by GeneDx and eight other laboratories). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 151 (1 homozygous) of 276982 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 3 of 24014 chromosomes (freq: 0.0001), Other in 4 of 6462 chromosomes (freq: 0.0006), Latino in 19 of 34416 chromosomes (freq: 0.0006), European Non-Finnish in 77 of 126584 chromosomes (freq: 0.0006), Ashkenazi Jewish in 20 (1 homozygous) of 10150 chromosomes (freq: 0.002), and South Asian in 28 of 30778 chromosomes (freq: 0.0009) while not observed in the East Asian and European Finnish populations. The variant was also identified by our laboratory in 1 individual with ovarian cancer, co-occurring with a pathogenic APC variant (c.-85-?_1408+?del/deletion of Promoter 1A/1B, exons 1 to 10) increasing the likelihood the variant has little clinical significance. The p.Leu420 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Met impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs 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 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. -

MUTYH-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;.;.;.;.;.;T;.;.;.;.;T

Eigen

Benign

0.085

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

.;.;D;.;D;D;D;D;D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.037

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.6

.;.;.;.;.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.0

N;N;N;N;N;N;N;N;N;N;N;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0070

D;T;T;T;T;T;D;T;T;D;D;.

Sift4G

Uncertain

0.015

D;T;T;T;T;T;T;T;T;D;T;T

Polyphen

0.045, 0.14, 0.18

.;.;.;.;.;.;B;B;.;.;B;.

Vest4

0.40

MVP

0.92

MPC

0.26

ClinPred

0.042

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over