chr1-45332440-G-C

Position:

• chr1-45332440-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.655C>G​(p.Arg219Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.54

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 1-45332440-G-C is Pathogenic according to our data. Variant chr1-45332440-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.655C>G	p.Arg219Gly	missense_variant	9/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.655C>G	p.Arg219Gly	missense_variant	9/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1243C>G		non_coding_transcript_exon_variant	13/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 247 of the MUTYH protein (p.Arg247Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal polyposis and cancer (PMID: 29330641, 31285513). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 587355). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 26694661, 31285513). This variant disrupts the p.Arg247 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been observed in individuals with MUTYH-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Oncology Laboratory, Hospital Clínico San Carlos	Jun 01, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2020

The p.R247G variant (also known as c.739C>G), located in coding exon 9 of the MUTYH gene, results from a C to G substitution at nucleotide position 739. The arginine at codon 247 is replaced by glycine, an amino acid with dissimilar properties. In one study, this alteration demonstrated partially retained functional activity (Shinmura K et al. Hum. Mutat., 2016 Apr;37:350-3). This alteration has also been detected in trans with a pathogenic MUTYH alteration in two siblings who presented with early-onset polyposis. One sibling was also diagnosed with early-onset colorectal cancer (Lorca V et al. Sci Rep, 2019 Jul;9:9814). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;.;.;.;.;T;.;.;.;T;.;T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.0091
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	0.93	.;.;.;.;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0080	D;D;D;D;D;T;T;T;T;T;D;T
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D;D;D;D;T;T
Polyphen		0.19, 0.30, 0.35	.;.;.;.;.;B;B;.;B;.;.;.
Vest4		0.86
MutPred		0.68		.;.;.;.;.;.;.;.;Loss of methylation at R247 (P = 0.0143);.;.;.;
MVP		0.90
MPC		0.38
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.90
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587782885; hg19: chr1-45798112;