1-45333471-C-T

Position:

chr1-45333471-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001048174.2(MUTYH):c.206G>A(p.Arg69Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 3.31

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.290G>A	p.Arg97Gln	missense_variant	3/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 linkuse as main transcript	c.206G>A	p.Arg69Gln	missense_variant	3/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.290G>A	p.Arg97Gln	missense_variant	3/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7 linkuse as main transcript	c.206G>A	p.Arg69Gln	missense_variant	3/16	1	NM_001048174.2	ENSP00000407590	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251486

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Arg97Gln variant in MUTYH has been previously reported in the compound heterozygous state in 1 individual with MUTYH-associated cancers and 1 with breast cancer (Maxwell 2015 PMID: 25503501; Tung 2015 PMD: 25186627). It has also been identified in 0.005% (1/18392) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 185512). Arginine (Arg) at position 97 is not conserved in mammals or evolutionarily distant species, and 4 mammals (Tibetian antelope, cow, sheep, and domestic goat) carry a glutamine (Gln) at this position, raising the possibility that this change may be tolerated. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, colon cancer, and/or colon polyps (Maxwell et al., 2015; Tung et al., 2015; Ricci et al., 2017); Also known as R94Q; This variant is associated with the following publications: (PMID: 27829682, 25503501, 25186627, 34426522) -

Familial adenomatous polyposis 2

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces arginine with glutamine at codon 97 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 3/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 19, 2024	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2023	Variant summary: MUTYH c.290G>A (p.Arg97Gln) results in a conservative amino acid change in 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 1.2e-05 in 251486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.290G>A has been reported in the literature in individuals affected with breast or colorectal cancer as well as unaffected controls (Maxwell_2014, Ricci_2016, Tung_2014, Dorling_2021, Pearlman_2021). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25503501, 25186627, 27829682, 33471991, 34250417). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 20, 2023	This missense variant replaces arginine with glutamine at codon 97 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer before the age of 50 (PMID: 25186627), an individual affected with early-onset colon cancer and early-onset breast cancer who also carried a second known pathogenic variant in MUTYH (PMID: 25503501), and an individual affected with colorectal neoplasia (PMID: 27829682). This variant has been identified in 3/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 21, 2024	The p.R97Q variant (also known as c.290G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 290. The arginine at codon 97 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in conjunction with a MUTYH founder mutation (phase unknown) in a patient diagnosed with early-onset colon cancer and bilateral breast cancer, as well as a family history of breast, colon, and uterine cancer, who had previously tested negative for mutations in BRCA1/2 by sequencing (Maxwell KN et al. Genet Med. 2015 Aug;17(8):630-8). This alteration was also detected in an individual diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33) and in 1/299 Italian colorectal cancer patients (Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315). Of note, this alteration is also known as p.R94Q in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MUTYH p.Arg97Gln variant was not identified in the literature nor was it identified in the COSMIC, Zhejiang Colon Cancer (LOVD), COGR, or UMD database. The variant was identified in dbSNP (ID: rs755653922) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹ and the Exome Aggregation Consortium database (August 8, 2016) in 1 of 121384 chromosomes (frequency: 0.000008). The variant was identified in the European (Non-Finnish) population in 1 of 66722 chromosomes (frequency: 0.00001), but not in the African, East Asian, Finnish, Latino, South Asian or Other populations. In Clinvar and Clinvitae, the variant was identified as uncertain significance by Ambry Genetics; InSiGHT Colon Cancer Gene Variant Database (LOVD) 1x as unknown. The p.Arg97 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant amino acid Glutamine (Gln) is present in cow, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Mar 08, 2023

The MUTYH c.290G>A (p.Arg97Gln) missense change has a maximum subpopulation frequency of 0.0054% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 25186627) and colorectal cancer (PMID: 27829682). It was observed to co-occur in unknown phase with a pathogenic MUTYH mutation (p.Gly396Asp) in an individual with a personal history of colorectal cancer and early-onset breast cancer, and a family history of colorectal cancer (PMID: 25503501). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

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

Eigen

Benign

0.069

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.4

.;.;.;.;.;L;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.56

Sift

Benign

0.034

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

Sift4G

Uncertain

0.031

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

Polyphen

0.52, 0.99, 0.99

.;.;.;.;.;P;D;.;D;.;.;.

Vest4

0.23

MutPred

0.57

.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0594);.;.;.;

MVP

0.96

MPC

0.28

ClinPred

0.95

GERP RS

4.4

Varity_R

0.33

gMVP

0.57

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