1-45331847-G-C

Position:

chr1-45331847-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001048174.2(MUTYH):c.916C>G(p.Pro306Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,601,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. P306T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0490

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035571367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.1000C>G	p.Pro334Ala	missense_variant, splice_region_variant	12/16	ENST00000710952.2
MUTYH	NM_001048174.2 linkuse as main transcript	c.916C>G	p.Pro306Ala	missense_variant, splice_region_variant	12/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.1000C>G	p.Pro334Ala	missense_variant, splice_region_variant	12/16		NM_001128425.2
MUTYH	ENST00000456914.7 linkuse as main transcript	c.916C>G	p.Pro306Ala	missense_variant, splice_region_variant	12/16	1	NM_001048174.2	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000131

AC:

AN:

228910

Hom.:

AF XY:

0.0000161

AC XY:

AN XY:

124154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000621

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:

0.00000981

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1449684

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719942

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000699

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:

0.0000181

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces proline with alanine at codon 334 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 an individual affected with multiple adenomatous and serrated polyps (PMID: 24470512). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 3/228910 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	Invitae	Jan 26, 2024	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 334 of the MUTYH protein (p.Pro334Ala). This variant is present in population databases (rs587778537, gnomAD 0.006%). This missense change has been observed in individual(s) with multiple adenomatous and serrated polyps (PMID: 24470512). ClinVar contains an entry for this variant (Variation ID: 183823). 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	MGZ Medical Genetics Center	Jul 20, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 20, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2023	This missense variant replaces proline with alanine at codon 334 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 an individual affected with multiple adenomatous and serrated polyps (PMID: 24470512). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 3/228910 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	May 24, 2024	The p.P334A variant (also known as c.1000C>G), located in coding exon 12 of the MUTYH gene, results from a C to G substitution at nucleotide position 1000. The proline at codon 334 is replaced by alanine, an amino acid with highly similar properties. This alteration has previously been detected in an individual with greater than 10 colon polyps (Guarinos C, Clin. Cancer Res. 2014 Mar; 20(5):1158-68), and was also detected in 1/1231 colorectal cancer patients and 0/93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This alteration was identified in 2/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This variant was also reported in 5/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 30, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2018

Variant summary: MUTYH c.1000C>G (p.Pro334Ala) results in a non-conservative amino acid change in the encoded protein sequence that lies 3 nucleotides away from an exon-intron junction. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 224868 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (1.3e-05 vs 0.0046), allowing no conclusion about variant significance. c.1000C>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis. However, these reports do not provide unequivocal conclusions about an association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.65

CADD

Benign

4.9

DANN

Benign

0.56

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.16

M_CAP

Benign

0.0054

MetaRNN

Benign

0.036

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

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.22

PROVEAN

Benign

0.39

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

REVEL

Benign

0.018

Sift

Benign

0.99

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

Sift4G

Benign

0.78

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

Polyphen

0.0

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

Vest4

0.19

MVP

0.23

MPC

0.11

ClinPred

0.026

GERP RS

-0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.090

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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