rs564930066

Positions:

• chr1-45332941-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001048174.2(MUTYH):​c.397G>C​(p.Asp133His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D133V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:1
• Conservation: PhyloP100: 2.65

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09248924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.481G>C	p.Asp161His	missense_variant	6/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.397G>C	p.Asp133His	missense_variant	6/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.481G>C	p.Asp161His	missense_variant	6/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.397G>C	p.Asp133His	missense_variant	6/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000132

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000998 AC: 25 AN: 250434 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461836 Hom.: 0 Cov.: 35 AF XY: 0.0000454 AC XY: 33 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74474

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:11 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 26, 2021	ACMG classification criteria: PS4 supporting, PM2 moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 30, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 161 of the MUTYH protein (p.Asp161His). This variant is present in population databases (rs564930066, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer, clinical features of MUTYH-associated polyposis (MAP), and/or endometrial cancer (PMID: 21424714, 25980754, 27443514, 30093976, 35264596; Invitae). 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: 140814). 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 tolerated. 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	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2024	The c.481G>C variant (also known as p.D161H), located in coding exon 6 of the MUTYH gene, results from a G to C substitution at nucleotide position 481. The aspartic acid at codon 161 is replaced by histidine, an amino acid with similar properties. This variant has been detected in conjunction with a MUTYH pathogenic variant or as homozygous in multiple unrelated individuals with clinical features of MUTYH-associated disease; however, the phase of the variants from the compound heterozygous cases is unknown (Ambry internal data). This variant was also reported in conjunction with MUTYH p.P405L in a patient with colorectal cancer (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). This alteration has also been reported in prostate and breast cancer cohorts who underwent hereditary multigene panel testing (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. However, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2022	Variant summary: MUTYH c.481G>C (p.Asp161His) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) 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 0.0001 in 250434 control chromosomes, predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database. This frequency is not higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0001 vs 0.0046), allowing no conclusion about variant significance. c.481G>C has been reported in the literature in individuals affected prostate cancer (Chan_2018), suspected lynch syndrome (Yurgelun_2015) without strong evidence for causality. Variant has been reported in a patient with colorectal cancer and a second pathogenic allele p.Y179C (Pitroski_2011). Additionally, the variant has also been reported in breast cancer cases and controls (Dorling_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25938944, 21777424, 25980754, 29684080, 30093976) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 28, 2022	The frequency of this variant in the general population, 0.00054 (19/35412 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer and/or polyposis (PMIDs: 25938944 (2015) and 25980754 (2015)), Cowden Syndrome (PMID: 29684080 (2018)), endometrial cancer (PMID: 27443514 (2016)), prostate cancer (PMID: 30093976 (2018)), breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)) and pediatric astrocytoma (PMID: 31970404 (2020)). Additionally, the variant has been reported in healthy individuals with no personal or family history of cancer (PMIDs: 21777424 (2011) and 33471991 (2021), see also LOVD (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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

MUTYH-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2023

The MUTYH c.481G>C variant is predicted to result in the amino acid substitution p.Asp161His. This variant was reported in individuals with suspected Lynch syndrome, kidney renal clear cell carcinoma, prostate cancer, or breast cancer (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table S7, Yehia et al. 2018. PubMed ID: 29684080; Table S2, Chan et al. 2018. PubMed ID: 30093976; Table S3, Guindalini et al. 2022. PubMed ID: 35264596). This variant was also reported along with an established pathogenic MUTYH variant in an individual with colorectal cancer (Pitroski et al. 2011. PubMed ID: 21424714). This variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45798613-C-G) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/140814). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.092	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.76, 0.53, 0.58	.;.;.;.;.;P;P;.;P;.;.
Vest4		0.30
MVP		0.94
MPC		0.18
ClinPred		0.058	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs564930066; hg19: chr1-45798613;