rs3219488

Positions:

• chr1-45331858-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001048174.2(MUTYH):​c.914-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,599,490 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: MUTYH NM_001048174.2 intron
• Scores: Splicing: ADA: 0.00001650
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 0.588

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_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-45331858-G-A is Benign according to our data. Variant chr1-45331858-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132703.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Uncertain_significance=3, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.914-9C>T		intron_variant		ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.914-9C>T		intron_variant		1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1502-9C>T		intron_variant				ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000388 AC: 87 AN: 223990 Hom.: 0 AF XY: 0.000353 AC XY: 43 AN XY: 121794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000601

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000539

Gnomad SAS exome AF: 0.0000349

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000532

Gnomad OTH exome AF: 0.000908

GnomAD4 exome AF: 0.000423 AC: 612 AN: 1447132 Hom.: 1 Cov.: 36 AF XY: 0.000434 AC XY: 312 AN XY: 718514

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000753

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000306

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000494

Gnomad4 OTH exome AF: 0.000335

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74496

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000398 Hom.: 0

Bravo AF: 0.000351

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 18, 2022	- -

Familial adenomatous polyposis 2 Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 02, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2024	Variant summary: MUTYH c.998-9C>T alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00039 in 224190 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00039 vs 0.0046), allowing no conclusion about variant significance. c.998-9C>T has been reported in the literature in individuals affected with colorectal/breast cancer (example, Aretz_2006, Kury_2007, Sulova_2007, Yurgelun_2015, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16557584, 17931073, 17524638, 25186627, 25980754). ClinVar contains an entry for this variant with a majority consensus as likely benign (Variation ID: 132703). 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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2014	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. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2019	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. -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MUTYH c.998-9C>T variant was identified in the heterozygous state in 3 of 3178 proband chromosomes (frequency: 0.0009) from individuals or families with Lynch syndrome-associated cancer and/or polyps, or FAP/AFAP (Yurgelun 2015, Aretz 2006). The variant was also identified in dbSNP (ID: rs3219488) as “With other allele”, ClinVar (classified as benign by GeneDx; as likely benign by Invitae, Color, Prevention Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano; and as uncertain significance by Integrated Genetics/Laboratory Corporation of America). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 103 of 251118 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 22150 chromosomes (freq: 0.00005), Other in 9 of 5946 chromosomes (freq: 0.002), Latino in 20 of 31626 chromosomes (freq: 0.0006), European Non-Finnish in 62 of 112936 chromosomes (freq: 0.0005), East Asian in 10 of 17302 chromosomes (freq: 0.0006), and South Asian in 1 of 28788 chromosomes (freq: 0.00004), while not observed in the Ashkenazi Jewish or European Finnish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.4
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs3219488; hg19: chr1-45797530;