chr1-45332464-C-T

Position:

chr1-45332464-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_001048174.2(MUTYH):c.631G>A(p.Val211Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,012 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V211A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10O:1

Conservation

PhyloP100: 4.53

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 5 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.631G>A	p.Val211Ile	missense_variant	9/16	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.631G>A	p.Val211Ile	missense_variant	9/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1219G>A		non_coding_transcript_exon_variant	13/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250556

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:5Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 09-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 13, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces valine with isoleucine at codon 239 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28961279, 32068069). This variant has been identified in 8/281912 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	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 239 of the MUTYH protein (p.Val239Ile). This variant is present in population databases (rs759295912, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28961279, 32068069). This variant is also known as p.Val225Ile. ClinVar contains an entry for this variant (Variation ID: 187628). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 15, 2023	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Sung 2017); Also reported as p.(Val225Ile); This variant is associated with the following publications: (PMID: 11801590, 23108399, 28961279) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 30, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2023	The p.V239I variant (also known as c.715G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 715. The valine at codon 239 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in one individual from a Taiwanese HBOC cohort (Sung PL et al. PLoS ONE, 2017 Sep;12:e0185615). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is highly 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 20, 2023	This missense variant replaces valine with isoleucine at codon 239 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28961279, 32068069). This variant has been identified in 8/281912 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 17, 2023

Variant summary: MUTYH c.715G>A (p.Val239Ile) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250556 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.715G>A has been reported in the literature in individuals affected with breast cancer or pancreatic cancer (Sung_2017, Kwong_2020, Zhu_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. Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

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

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.77

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

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.1

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

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.92

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

REVEL

Uncertain

0.48

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.010

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

Polyphen

0.76, 0.52, 0.57

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

Vest4

0.33

MutPred

0.75

.;.;.;.;.;.;.;.;Gain of sheet (P = 0.0827);.;.;.;

MVP

0.87

MPC

0.16

ClinPred

0.31

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.39

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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