1-45330551-G-A

Position:

• chr1-45330551-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001048174.2(MUTYH):​c.1399C>T​(p.Arg467Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,608,484 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R467H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000020 (1 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 4.47

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1399C>T	p.Arg467Cys	missense_variant	15/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1399C>T	p.Arg467Cys	missense_variant	15/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1987C>T		non_coding_transcript_exon_variant	19/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000374 AC: 9 AN: 240490 Hom.: 1 AF XY: 0.0000154 AC XY: 2 AN XY: 129842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000103

Gnomad FIN exome AF: 0.0000479

Gnomad NFE exome AF: 0.0000463

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1456336 Hom.: 1 Cov.: 31 AF XY: 0.0000166 AC XY: 12 AN XY: 723936

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

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: 0.0000752 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 495 of the MUTYH protein (p.Arg495Cys). This variant is present in population databases (rs587781668, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 141339). 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 disruptive. 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	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 27, 2023	The MUTYH c.1483C>T (p.Arg495Cys) missense change has a maximum subpopulation frequency of 0.010% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with a personal history of pancreatic and prostate cancers and a family history of breast cancer (PMID: 34034685). To our knowledge, this variant has not been reported in individuals with MUTYH-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces arginine with cysteine at codon 495 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic cancer and prostate cancer (PMID: 34034685). This variant has been identified in 11/271888 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 26, 2019	The MUTYH c.1483C>T; p.Arg495Cys variant (rs587781668), to our knowledge, is not reported in the medical literature but is reported as uncertain significance in the ClinVar database (Variation ID: 141339). This variant is found in the general population with an overall allele frequency of 0.004% (11/271,888 alleles with 1 homozygote) in the Genome Aggregation Database. The arginine at codon 495 is moderately conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2023	This missense variant replaces arginine with cysteine at codon 495 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pancreatic cancer and prostate cancer (PMID: 34034685). This variant has been identified in 11/271888 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	Oct 24, 2022	The p.R495C variant (also known as c.1483C>T), located in coding exon 15 of the MUTYH gene, results from a C to T substitution at nucleotide position 1483. The arginine at codon 495 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in a patient with a personal history of pancreatic and prostate cancer and was classified as a variant of uncertain significance by the authors (Rapposelli IG et al. BMC Cancer, 2021 May;21:611). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;.;.;.;.;.;D;.;.;.;.;D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	.;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.99, 0.80	.;.;.;.;.;.;D;D;.;.;P;.
Vest4		0.67
MutPred		0.56		.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 6e-04);.;
MVP		0.95
MPC		0.40
ClinPred		0.60	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.27
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587781668; hg19: chr1-45796223; COSMIC: COSV105235968; COSMIC: COSV105235968;