1-45334495-G-A

Position:

• chr1-45334495-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_001048174.2(MUTYH):​c.11C>T​(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,614,074 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (7 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:13 O:1
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046937466).
• BP6: Variant 1-45334495-G-A is Benign according to our data. Variant chr1-45334495-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41759.We mark this variant Likely_benign, oryginal submissions are: {Benign=10, Uncertain_significance=3, Likely_benign=2, not_provided=1}. Variant chr1-45334495-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 7 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	UniProt
MUTYH	NM_001128425.2	c.53C>T	p.Pro18Leu	missense_variant	2/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.11C>T	p.Pro4Leu	missense_variant	2/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.53C>T	p.Pro18Leu	missense_variant	2/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.11C>T	p.Pro4Leu	missense_variant	2/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0136

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00107 AC: 269 AN: 251474 Hom.: 4 AF XY: 0.00104 AC XY: 142 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0126

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000427 AC: 624 AN: 1461838 Hom.: 7 Cov.: 31 AF XY: 0.000439 AC XY: 319 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000682 Hom.: 0

Bravo AF: 0.000808

ExAC AF: 0.00111 AC: 135

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:13 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2021	This variant is associated with the following publications: (PMID: 22703879, 11295288, 22641385, 25980754, 18422726, 18811933, 25525159, 16929514, 25820570, 26684191, 17252231, 27443514, 26332594, 24728327, 17703316, 27600092, 29330641, 29879026, 30333958, 29667044) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: The MUTYH c.53C>T (p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.001112 (135/121410 chrs tested), predominantly in individuals of East Asian descent with a frequency of 0.013 (114/8654 chrs, including 2 homozygotes). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. Most of the published reports indicate that c.74G>A co-occurs in cis with c.74G>A(G25DL). Although c.[53C>T; 74G>A] haplotype has been reported to be enriched in sporadic CRC pts compared to controls (Chen, 2008), in functional studies both the complex allele and its compounds were shown to retain complementation ability and were considered to be functionally neutral. In addition, several reported CRC pts carried known pathogenic variants (APC c.3595_3596delAA (p.Lys1199Glufs), MSH6 c.3724_3726del (p.Arg1242del) , that could have explain CRC phenotype in these families (Taki, 2016, Ring, 2012). Lastly, several reputable databases/diagnostic centers classified the variant of interest as VUS/ Benign. Taking together, by applying ACMG rules, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MUTYH: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 28, 2023	- -

Familial adenomatous polyposis 2 Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Uncertain:1 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.3% (114/8654) East Asian chromosomes - common haplotype with Gly25Asp -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 02, 2017	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 14, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 03, 2017	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. -

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.Pro18Leu variant was identified in 20 of 1686 proband chromosomes (frequency: 0.01) from individuals or families from Asian individuals (Korean, Chinese, Japanese) with colorectal, endometrial and adenomatous polyposis cancer (Ring 2016, Taki 2016, Chen 2008, Kim 2007, Yanaru-Fujisawa 2008, Zhang 2006). The variant was also identified in the following databases: dbSNP (ID: rs79777494) as With other allele, ClinVar (classified as benign by Invitae, Ambry Genetics, Integrated Genetics/Laboratory Corporation of America; as uncertain significance by GeneDx, and two clinical laboratories), Clinvitae, COGR, and MutDB. The variant was not identified in Cosmic, or UMD-LSDB databases. The variant was identified in control databases in 288 of 277220 chromosomes (4 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 2 of 6462 chromosomes (freq: 0.0003), European in 4 of 126714 chromosomes (freq: 0.00003), East Asian in 250 of 18870 chromosomes (freq: 0.01), and South Asian in 32 of 30782 chromosomes (freq: 0.001); it was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Pro18 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 occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was identified in co-occurrence on the same allele as another MUTYH variant, p.Gly25Asp. Two studies suggest that this haplotype variant allele (containing both p.Pro18Leu and p.Gly25Asp variants) increases the risk of gastric cancer, with significantly higher frequencies of the variant haplotype observed in affected cases than in healthy controls (Chen 2008, Zhang 2006). In addition, a functional study by Chen (2008) found that the haplotype variant allele had a partial effect on protein mitochondrial transport as compared to wild type MUTYH protein. This effect, however, was not found when each variant was tested individually, suggesting an additive effect of the combined variants on the mitochondrial targeting sequences domain of the MUTYH protein. In addition, several studies identify the variant co-occurring with known pathogenic variants (APC c.3595_3596delAA (p.Lys1199Glufs), MSH6 c.3724_3726del (p.Arg1242del), increasing the likelihood that the p.Gly25Asp variant does not have clinical significance (Ring 2016, Taki 2016). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.079	.;.;.;.;.;.;T;.;.;.;.;.;T;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	.;.;D;.;D;D;D;T;T;D;D;D;D;D;D
MetaRNN	Benign	0.0047	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.74	.;.;.;.;.;.;N;N;N;.;.;.;.;.;.
MutationTaster	Benign	0.82	D;D;D;D;D;D;D;D;D;D;D;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	D;N;N;N;N;N;N;N;N;D;N;D;N;N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;D;T;D;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;D;T;D;T;T;T
Polyphen		0.0060, 0.047, 0.028	.;.;.;.;.;.;B;B;.;.;B;.;.;.;.
Vest4		0.40
MVP		0.83
MPC		0.12
ClinPred		0.070	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.12

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

Other links and lift over

dbSNP: rs79777494; hg19: chr1-45800167;