rs564930066

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001048174.2(MUTYH):c.397G>C(p.Asp133His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. D133V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:13B:1

Conservation

PhyloP100: 2.65

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09248924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.397G>C	p.Asp133His	missense_variant	Exon 6 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.397G>C	p.Asp133His	missense_variant	Exon 6 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.985G>C		non_coding_transcript_exon_variant	Exon 10 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000998

AC:

AN:

250434

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000112

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:13Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:6

Dec 30, 2015

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 161 of the MUTYH protein (p.Asp161His). This variant is present in population databases (rs564930066, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer, clinical features of MUTYH-associated polyposis (MAP), and/or endometrial cancer (PMID: 21424714, 25980754, 27443514, 30093976, 35264596, 35980532; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 140814). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Sep 26, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 supporting, PM2 moderate -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with histidine at codon 161 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three biallelic individuals affected with colorectal cancer and/or MUTYH-associated polyposis (PMID: 21424714, 25938944; ClinVar Accession: SCV000172897.8). This variant has also been detected in two individuals who were tested for Lynch syndrome (PMID: 25980754, 38060977), two individuals affected with endometrial cancer (PMID: 27443514), an individual affected with prostate cancer (PMID: 30093976), an individual affected with either Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 29684080), and several individuals affected with breast cancer (PMID: 35264596). In an international breast cancer case-control meta-analysis, this variant was detected in 5/60466 cases and 14/53461 unaffected controls (OR=0.316, 95%CI 0.114 to 0.877, p-value=0.022; PMID: 33471991). This variant has been identified in 29/281806 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. -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1Benign:1

Sep 10, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 17, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.481G>C variant (also known as p.D161H), located in coding exon 6 of the MUTYH gene, results from a G to C substitution at nucleotide position 481. The aspartic acid at codon 161 is replaced by histidine, an amino acid with similar properties. This variant has been detected in conjunction with a MUTYH pathogenic variant or as homozygous in multiple unrelated individuals with clinical features of MUTYH-associated disease; however, the phase of the variants from the compound heterozygous cases is unknown (Ambry internal data). This variant was also reported in conjunction with MUTYH p.P405L in a patient with colorectal cancer (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). This alteration has also been reported in prostate and breast cancer cohorts who underwent hereditary multigene panel testing (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. However, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Mar 21, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:3

Sep 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Co-observed with a MUTYH variant, phase unknown, in a patient with colorectal cancer and polyps (PMID: 25938944; personal communication with authors); Observed in heterozygous state in individuals with polyposis, breast cancer, astrocytoma, endometrial cancer, and prostate cancer (PMID: 30093976, 35264596, 35980532, 27443514, 31970404, 38254803); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21777424, 25980754, 29684080, 30093976, 33471991, 17161978, Giacomazzi2022[preprint], 35264596, 27443514, 21424714, 25938944, 38254803, 31970404, 35980532) -

Feb 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.481G>C p.Asp161His variant (rs564930066; ClinVar Variation ID: 140814), also known as D134H, has been identified in cohorts of individuals affected with colon (Yehia 2018), endometrial (Ring 2016), prostate (Chan 2018), and breast (Guindalini 2022, Pereira 2022, Dorling 2021) cancer, thought additional evidence of causality is not presented. This variant has also been identified in controls (Dorling 2021) and is found in the Admixed American population with an allele frequency of 0.05% (19/35412 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.351). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Chan GHJ et al. Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. Oncotarget. 2018 Jul 17;9(55):30649-30660. PMID: 30093976 Dorling L et al. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med. 2021 Feb 4;384(5):428-439 PMID: 33471991 Guindalini RSC et al. Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. Sci Rep. 2022 Mar 9;12(1):4190. PMID: 35264596 Pereira JZ et al. Frequency of germline genetic variants in women with a personal or family history of breast cancer from Brazil. Mol Biol Rep. 2022 Oct;49(10):9509-9520. PMID: 35980532. Ring KL et al. Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. Mod Pathol. 2016 Nov;29(11):1381-1389. PMID: 27443514 Yehia L et al. Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. PLoS Genet. 2018 Apr 23;14(4):e1007352. PMID: 29684080 -

Oct 28, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.00054 (19/35412 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer and/or polyposis (PMIDs: 25938944 (2015) and 25980754 (2015)), Cowden Syndrome (PMID: 29684080 (2018)), endometrial cancer (PMID: 27443514 (2016)), prostate cancer (PMID: 30093976 (2018)), breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)) and pediatric astrocytoma (PMID: 31970404 (2020)). Additionally, the variant has been reported in healthy individuals with no personal or family history of cancer (PMIDs: 21777424 (2011) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). 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. -

not specified

Uncertain:2

Aug 18, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUTYH c.481G>C (p.Asp161His) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250434 control chromosomes, predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database. This frequency is not higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0001 vs 0.0046), allowing no conclusion about variant significance. c.481G>C has been reported in the literature in individuals affected prostate cancer (Chan_2018), suspected lynch syndrome (Yurgelun_2015) without strong evidence for causality. Variant has been reported in a patient with colorectal cancer and a second pathogenic allele p.Y179C (Pitroski_2011). Additionally, the variant has also been reported in breast cancer cases and controls (Dorling_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MUTYH-related disorder

Uncertain:1

Nov 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MUTYH c.481G>C variant is predicted to result in the amino acid substitution p.Asp161His. This variant was reported in individuals with suspected Lynch syndrome, kidney renal clear cell carcinoma, prostate cancer, or breast cancer (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table S7, Yehia et al. 2018. PubMed ID: 29684080; Table S2, Chan et al. 2018. PubMed ID: 30093976; Table S3, Guindalini et al. 2022. PubMed ID: 35264596). This variant was also reported along with an established pathogenic MUTYH variant in an individual with colorectal cancer (Pitroski et al. 2011. PubMed ID: 21424714). This variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45798613-C-G) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/140814). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.15

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

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.059

MetaRNN

Benign

0.092

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

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

1.6

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

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.21

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

Sift4G

Benign

0.19

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

Polyphen

0.76, 0.53, 0.58

.;.;.;.;.;P;P;.;P;.;.

Vest4

0.30

MVP

0.94

MPC

0.18

ClinPred

0.058

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.62

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