rs777335285

Variant names:

• chr1-45332439-C-A
• NM_001048174.2:c.656G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45332439-C-A
• chr1-45332439-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_001048174.2(MUTYH):​c.656G>T​(p.Arg219Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R219G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.46

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_pathogenic. Variant got 6 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, 16 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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 rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.656G>T	p.Arg219Leu	missense_variant	Exon 9 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.656G>T	p.Arg219Leu	missense_variant	Exon 9 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1244G>T		non_coding_transcript_exon_variant	Exon 13 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1

Aug 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 247 of the MUTYH protein (p.Arg247Leu). 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. 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 (PMID: 31285513; Invitae), which suggests that this may be a clinically significant amino acid residue. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R247L variant (also known as c.740G>T), located in coding exon 9 of the MUTYH gene, results from a G to T substitution at nucleotide position 740. The arginine at codon 247 is replaced by leucine, an amino acid with dissimilar properties. 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 available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;.;.;.;.;T;.;.;.;T;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.71	.;.;.;.;.;N;.;.;.;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.012	D;T;D;D;D;T;T;D;T;T;T;T
Sift4G	Uncertain	0.053	T;D;T;T;T;T;D;D;T;D;T;T
Polyphen		0.0080, 0.014, 0.018	.;.;.;.;.;B;B;.;B;.;.;.
Vest4		0.85
MutPred		0.63		.;.;.;.;.;.;.;.;Loss of methylation at R247 (P = 0.0143);.;.;.;
MVP		0.84
MPC		0.52
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.84
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45798111;