chr1-45332692-T-C

Position:

• chr1-45332692-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001048174.2(MUTYH):​c.493-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MUTYH NM_001048174.2 splice_region, intron
• Scores: Splicing: ADA: 0.9799
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3
• Conservation: PhyloP100: 0.702

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45332692-T-C is Pathogenic according to our data. Variant chr1-45332692-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183746.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=6, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.493-5A>G		splice_region_variant, intron_variant		ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.493-5A>G		splice_region_variant, intron_variant		1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1081-5A>G		splice_region_variant, intron_variant				ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461850 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change falls in intron 7 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs758377868, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of MUTYH-associated polyposis (PMID: 10612827, 21520333, 32133419, 33011440; Invitae; external communication). 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: 183746). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 32133419, 33011440; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2021	Variant summary: MUTYH c.577-5A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 3 acceptor site. Two predict the variant weakens a 3 acceptor site. Two predict the variant creates a 3 cryptic acceptor site. Additionally, at least two RNA studies report this variant causes aberrant splicing and shows the inclusion of the last four nucleotides of intron 7 [r.576_577ins(577-4_577-1)], which presumably would generate a truncated protein (p.Val165Serfs*61) (Landrith_2020, Rofes_2020). The variant allele was found at a frequency of 4e-06 in 252164 control chromosomes (gnomAD and publication data). c.577-5A>G has been reported in the literature in two individuals affected with severe polyposis and one homozygous individual with personal and family records of colorectal polyps (Landrith_2020, Rofes_2020). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3), likely pathogenic (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This variant causes an A to G nucleotide substitution at the -5 position of intron 7 of the MUTYH gene. Functional RNA studies have shown that this variant causes aberrant splicing and results in a partial retention of intron 7 (r.576_577ins577-4_577-1), which is predicted to cause a frameshift and premature protein truncation (PMID: 32133419, 33011440). This variant has been observed in the homozygous state and compound heterozygous state in multiple individuals affected with severe polyposis (PMID: 32133419, 33011440, 34704405). This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 12, 2022	The c.577-5A>G intronic pathogenic mutation results from an A to G substitution 5 nucleotides upstream from coding exon 8 in the MUTYH gene. This variant has been identified in conjunction with pathogenic MUTYH mutations in probands with adenomatous polyposis (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. In a study involving RNA extraction for RT-PCR and Sanger sequencing of 10 hereditary cancer genes, incomplete disruption of the natural splice site was observed for this alteration (Rofes P et al. J Mol Diagn. 2020 12;22:1453-1468). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2023	This variant causes an A to G nucleotide substitution at the -5 position of intron 7 of the MUTYH gene. Functional RNA studies have shown that this variant causes aberrant splicing and results in a partial retention of intron 7 (r.576_577ins577-4_577-1), which is predicted to cause a frameshift and premature protein truncation (PMID: 32133419, 33011440). This variant has been observed in the homozygous state and compound heterozygous state in multiple individuals affected with severe polyposis (PMID: 32133419, 33011440, 34704405). This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2023	Published functional studies demonstrate aberrant splicing (Rofes et al., 2020; Landrith et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33011440, 34704405, 35668106, 32133419) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	18
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: -1
DS_AL_spliceai		0.64		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs758377868; hg19: chr1-45798364;