rs35352891

Positions:

• chr1-45331729-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_001048174.2(MUTYH):​c.1034C>T​(p.Ala345Val) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,614,186 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A345S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (6 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:14
• Conservation: PhyloP100: 6.96

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009427875).
• BP6: Variant 1-45331729-G-A is Benign according to our data. Variant chr1-45331729-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 41751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.1118C>T	p.Ala373Val	missense_variant	12/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.1034C>T	p.Ala345Val	missense_variant	12/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.1118C>T	p.Ala373Val	missense_variant	12/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.1034C>T	p.Ala345Val	missense_variant	12/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000383 AC: 96 AN: 250472 Hom.: 1 AF XY: 0.000376 AC XY: 51 AN XY: 135772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00462

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000209 AC: 305 AN: 1461828 Hom.: 6 Cov.: 33 AF XY: 0.000219 AC XY: 159 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00625

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74506

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.000344

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:1 Benign:4

Pathogenic, flagged submission	literature only	GeneReviews	Oct 08, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MUTYH p.Ala373Val variant was identified in 4 of 256 proband chromosomes (frequency: 0.016) from Japanese or Korean individuals or families with adenomatous polyposis, and was identified in 4 of 192 control chromosomes (frequency: 0.021) from healthy individuals (Kim 2007; Yanaru-Fujisawa 2008); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. Functional studies assessing glycosylase activity of the MUTYH protein showed that the p.Ala373Val variant retained its activity (Goto 2010, Yanaru-Fujisawa 2008). The variant was also identified in dbSNP (rs35352891) “With allele of uncertain significance”, with a minor allele frequency of 0.001(1000 Genomes Project), HGMD, and the ClinVar database (as a variant of unknown significance). The p.Ala373 residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 18, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 11, 2018	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. -
Uncertain significance, flagged submission	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 16, 2021	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2023	Variant summary: MUTYH c.1118C>T (p.Ala373Val) results in a non-conservative amino acid change located in the MutY, C-terminal domain (IPR029119) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 250664 control chromosomes, predominantly at a frequency of 0.0046 within the East Asian subpopulation in the gnomAD database. The frequency within the East Asian subpopulation is equal to the estimated maximal expected allele frequency for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0046). In addition, the variant was found at an even higher frequency of 0.0091 in Japanese controls in the HGVD-Kyoto database, suggesting that this variant is a benign polymorphism found primarily in individuals of East Asian ethnicity. c.1118C>T has been reported in affected individuals in the literature, including at least one occurrence in an individual presenting with colorectal polyposis, who was homozygous for both the variant of interest, but also the likely pathogenic variant p.G272E (Yanaru-Fujisawa_2008). Cosegregation studies associating the variant of interest with disease have not, to our knowledge, been performed. Additionally, a case-control study showed the variant at a similar frequency in cases compared to controls, showing the variant to not be associated with colorectal cancer risk in the Japanese cohort (Fujita_2020). The reports in patients in the literature do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least two publications report experimental evidence indicating that the variant does not significantly affect DNA-glycosylase activity (e.g. Goto_2010, Yanaru-Fujisawa_2008). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (benign/likely benign, n=9; uncertain significance, n=2; pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MUTYH: BS3:Supporting, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 25, 2022	- -
Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jan 02, 2024	This variant has been classified as likely benign based on a combination of factors including bioinformatic predictions (REVEL 0.470), population frequency in gnomAD (popmax EAS 0.456), and functional assay results (PMID: 20848659). -

MUTYH-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;.;.;.;T;.;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.0094	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.11	T;T;T;D;T;D;T;T;T;.
Sift4G	Uncertain	0.043	D;T;D;D;D;T;T;T;T;T
Polyphen		0.086, 0.64, 0.51	.;.;.;.;.;B;P;.;P;.
Vest4		0.56
MVP		0.94
MPC		0.22
ClinPred		0.12	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35352891; hg19: chr1-45797401; COSMIC: COSV58344165; COSMIC: COSV58344165;