chr1-45329400-C-T

Position:

• chr1-45329400-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001048174.2(MUTYH):​c.1472G>A​(p.Arg491Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,074 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. 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. R491W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: -1.18

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09537077).
• BP6: Variant 1-45329400-C-T is Benign according to our data. Variant chr1-45329400-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127841.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1472G>A	p.Arg491Gln	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.1472G>A	p.Arg491Gln	missense_variant	16/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.*215G>A		non_coding_transcript_exon_variant	21/21			ENSP00000499896.1
ENSG00000288208	ENST00000671898	n.*215G>A		3_prime_UTR_variant	15/15			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152080 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

Gnomad4 AFR AF: 0.0000963

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 519 of the MUTYH protein (p.Arg519Gln). This variant is present in population databases (rs369410616, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 31090900). ClinVar contains an entry for this variant (Variation ID: 127841). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	Counsyl	Aug 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces arginine with glutamine at codon 519 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: 31090900, 33471991). In a large international case-control study, this variant was reported in 4/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 6/282814 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 provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Nones 2019); This variant is associated with the following publications: (PMID: 31090900) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 17, 2024	The MUTYH c.1556G>A (p.Arg519Gln) variant has been reported in the published literature in individuals with breast cancer and in reportedly healthy individuals (PMIDs: 33471991 (2021), 31090900 (2019), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH). The frequency of this variant in the general population, 0.000021 (6/282814 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2021	Variant summary: MUTYH c.1556G>A (p.Arg519Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1556G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Nones_2019). A risk association study showed that this variant is not associated with Hereditary Breast And Ovarian Cancer Syndrome (Dorling_2021, LOVD database, p=0.6). Co-occurrence with a pathogenic variant has been reported (BRCA1 c.5244_5245delAA, p.Lys1748fs, Nones_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=3, likely benign n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 01, 2022	This missense variant replaces arginine with glutamine at codon 519 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: 31090900, 33471991). In a large international case-control study, this variant was reported in 4/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 6/282814 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 27, 2017	This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.8
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.78	.;.;T;.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.095	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.8	.;.;.;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.89	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.16
Sift	Uncertain	0.015	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.064	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.76, 1.0, 1.0	.;.;.;.;.;.;P;D;.;.;D;.
Vest4		0.092
MVP		0.82
MPC		0.13
ClinPred		0.083	T
GERP RS		-0.86
Varity_R		0.044
gMVP		0.21

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: rs369410616; hg19: chr1-45795072;