rs3219496

Positions:

• chr1-45329371-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_001048174.2(MUTYH):​c.1501C>A​(p.Leu501Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000808 in 1,614,220 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L501L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (18 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 1.64

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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073990226).
• BP6: Variant 1-45329371-G-T is Benign according to our data. Variant chr1-45329371-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 41756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000732 (1070/1461888) while in subpopulation AMR AF= 0.0223 (996/44724). AF 95% confidence interval is 0.0211. There are 18 homozygotes in gnomad4_exome. There are 442 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 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	Protein	UniProt
MUTYH	NM_001048174.2	c.1501C>A	p.Leu501Met	missense_variant	16/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1501C>A	p.Leu501Met	missense_variant	16/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.*244C>A		non_coding_transcript_exon_variant	21/21			ENSP00000499896.1
ENSG00000288208	ENST00000671898	n.*244C>A		3_prime_UTR_variant	15/15			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152214 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

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: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00346 AC: 870 AN: 251490 Hom.: 16 AF XY: 0.00252 AC XY: 343 AN XY: 135918

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000732 AC: 1070 AN: 1461888 Hom.: 18 Cov.: 31 AF XY: 0.000608 AC XY: 442 AN XY: 727246

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152332 Hom.: 2 Cov.: 31 AF XY: 0.00181 AC XY: 135 AN XY: 74492

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000484 Hom.: 0

Bravo AF: 0.00284

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 07, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 09, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 28, 2018	- -

not provided Benign:4

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 17, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2021	This variant is associated with the following publications: (PMID: 24728327, 21167187, 25820570, 22703879, 21153778, 28944238) -

Familial adenomatous polyposis 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 30, 2016	- -

Carcinoma of colon Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MUTYH p.Leu529Met variant was identified in the literature, although the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs3219496) as “with other allele”, ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Pathway Genomics and 3 other submitters; and as benign by Invitae, Color, PreventionGenetics and 2 other submitters). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 893 of 282,882 chromosomes (16 homozygous) at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 852 of 35,440 chromosomes (freq: 0.02), Other in 16 of 7226 chromosomes (freq: 0.002), African in 15 of 24,966 chromosomes (freq: 0.0006), East Asian in 3 of 19,954 chromosomes (freq: 0.0002), European in 6 of 129,186 chromosomes (freq: 0.00005), and South Asian in 1 of 30,616 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish or Finnish populations. Site-directed mutagenesis experiments demonstrated that the variant did not alter the functional activity of MUTYH in E. coli cells (Komine 2015). The p.Leu529 residue is 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Pathway Genomics	Dec 15, 2014	- -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	.;.;T;.;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0074	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.64	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.24
Sift	Benign	0.059	T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.89, 0.94, 0.92	.;.;.;.;.;.;P;P;.;.;P;.
Vest4		0.47
MVP		0.81
MPC		0.37
ClinPred		0.021	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.40

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: rs3219496; hg19: chr1-45795043;