1-45332621-C-T

Position:

• chr1-45332621-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000456914.7(MUTYH):​c.559G>A​(p.Val187Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V187L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MUTYH ENST00000456914.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a helix (size 16) in uniprot entity MUTYH_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000456914.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 1-45332621-C-T is Pathogenic according to our data. Variant chr1-45332621-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 184952.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_001128425.2	c.643G>A	p.Val215Met	missense_variant	8/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.559G>A	p.Val187Met	missense_variant	8/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.643G>A	p.Val215Met	missense_variant	8/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.559G>A	p.Val187Met	missense_variant	8/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251426 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461868 Hom.: 0 Cov.: 36 AF XY: 0.0000234 AC XY: 17 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000363 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19032956, 27014339, 19394335, 24834277, 28577310, 34426522, 19732775, 20618354) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 18, 2022	The frequency of this variant in the general population, 0.00029 (9/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with MUTYH associated polyposis co-occurring with an additional pathogenic MUTYH variant (PMID: 19032956 (2009), 19394335 (2009)). In a large breast cancer association study, the variant was reported in affected and unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/MUTYH). 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, this variant is classified as likely pathogenic. -

Familial adenomatous polyposis 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the MUTYH protein (p.Val215Met). This variant is present in population databases (rs776487884, gnomAD 0.03%). This missense change has been observed in individual(s) with MUTYH-associated polyposis syndrome (PMID: 19032956, 19732775, 20618354; Invitae; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 184952). 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. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This missense variant replaces valine with methionine at codon 215 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 colorectal cancer with more than 100 colorectal polyps and a pathogenic MUTYH co-variant c.884C>T (p.Pro295Leu)(PMID: 20618354). This variant has also been identified in the compound heterozygous state in an individual affected with multiple adenomatous polyps and in the homozygous state in an individual affected with colon cancer and colorectal polyps (communication with an external laboratory; ClinVar SCV000214928.5). This variant has been identified in 12/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 28, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 06, 2023	The p.V215M variant (also known as c.643G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 643. The valine at codon 215 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in both a homozyous state and in conjunction with a likely pathogenic variant in MUTYH in individuals with polyposis (Ambry internal data). This alteration has also been reported in conjunction with a MUTYH pathogenic variant in an individual diagnosed at age 30 with colorectal cancer as well as numerous colorectal and duodenal adenomas and has a high probability of being in trans given it has co-occurred with multiple different mutations (Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2023	This missense variant replaces valine with methionine at codon 215 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 colorectal cancer with more than 100 colorectal polyps and a pathogenic MUTYH co-variant c.884C>T (p.Pro295Leu)(PMID: 20618354). This variant has also been identified in the compound heterozygous state in an individual affected with multiple adenomatous polyps and in the homozygous state in an individual affected with colon cancer and colorectal polyps (communication with an external laboratory; ClinVar SCV000214928.5). This variant has been identified in 12/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;.;.;.;.;D;.;.;.;T;.;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;.;.;.;.;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	N;N;N;N;N;N;N;N;N;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.94
MVP		0.98
MPC		0.55
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.87
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs776487884; hg19: chr1-45798293; COSMIC: COSV58344172; COSMIC: COSV58344172;