rs781222233

Positions:

• chr1-45332886-TCCTATTTCCCCTA-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.420+19_420+31del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MUTYH NM_001048174.2 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.76

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45332886-TCCTATTTCCCCTA-T is Pathogenic according to our data. Variant chr1-45332886-TCCTATTTCCCCTA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332886-TCCTATTTCCCCTA-T is described in Lovd as [Pathogenic]. Variant chr1-45332886-TCCTATTTCCCCTA-T is described in Lovd as [Likely_pathogenic]. Variant chr1-45332886-TCCTATTTCCCCTA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001048174.2	c.420+19_420+31del		intron_variant		ENST00000456914.7
MUTYH	NM_001128425.2	c.504+19_504+31del		intron_variant		ENST00000710952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000456914.7	c.420+19_420+31del		intron_variant		1	NM_001048174.2	A1
MUTYH	ENST00000710952.2	c.504+19_504+31del		intron_variant			NM_001128425.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251048 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135684

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461820 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727210

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 24, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 20628285; Invitae). ClinVar contains an entry for this variant (Variation ID: 406825). This variant is also known as IVS6+19-31del13. This variant has been observed in individual(s) with MUTYH-associated polyposis (PMID: 16890597, 19732775, 20628285, 21520333). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs781222233, gnomAD 0.002%). This sequence change falls in intron 6 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 likely results in a shortened protein product. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This variant causes a 13 base pair deletion in intron 6 of the MUTYH gene. An RNA study found this variant resulted in the in-frame skipping of exon 6 (PMID: 20628285). This variant has been reported in compound heterozygous and homozygous carriers with polyposis and/or colorectal cancer (PMID: 16890597, 19732775, 20618354, 20628285, 26446593, 27829682). In particular, this variant was observed in the compound heterozygous state with a pathogenic variant, c.1437_1439del, in an individual affected with polyps and colorectal cancer (PMID: 20628285). The proband's mother, who was heterozygous for this variant, as well as the proband's sister, who was heterozygous for c.1437_1439del variant, were unaffected with polyps and colorectal cancer. This variant was also observed in homozygosity in three siblings in a different family (PMID: 20628285). Their heterozygous mother, father, and one sibling were unaffected with polyps and colorectal cancer (PMID: 20628285). This variant has been identified in 2/251048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 25, 2022	The MUTYH c.504+19_504+31del variant (rs781222233) is reported in the literature in the compound heterozygous or homozygous state in several individuals and families affected with MUTYH-associated polyposis (Di Gregorio 2006, Fostira 2010, Jones 2009, Morak 2010, Papp 2016, Vogt 2009). This variant is also reported in ClinVar (Variation ID: 406825), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant that deleted 13 nucleotides of intron 6, and in vitro functional analyses demonstrate skipping of exon 6, leading to an in-frame deletion that removes part of the critical glycosylase catalytic domain (Fostira 2010). Based on available information, this variant is considered to be pathogenic. References: Di Gregorio C et al. Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis. Gastroenterology. 2006 Aug;131(2):439-44. PMID: 16890597. Fostira F et al. An in-frame exon-skipping MUTYH mutation is associated with early-onset colorectal cancer. Dis Colon Rectum. 2010 Aug;53(8):1197-201. PMID: 20628285. Jones N et al. Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology. 2009 Aug;137(2):489-94, 494.e1; quiz 725-6. PMID: 19394335. Morak M et al. MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet. 2010 Oct;78(4):353-63. PMID: 20618354. Papp J et al. Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. Fam Cancer. 2016 Jan;15(1):85-97. PMID: 26446593. Vogt S et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10. PMID: 19732775. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MUTYH: PM3:Strong, PM2, PS3:Supporting, PS4:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 08, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 14, 2023	This variant causes a 13 base pair deletion in intron 6 of the MUTYH gene. An RNA study found this variant resulted in the in-frame skipping of exon 6 (PMID: 20628285). This variant has been reported in compound heterozygous and homozygous carriers with polyposis and/or colorectal cancer (PMID: 16890597, 19732775, 20618354, 20628285, 26446593, 27829682). In particular, this variant was observed in the compound heterozygous state with a pathogenic variant, c.1437_1439del, in an individual affected with polyps and colorectal cancer (PMID: 20628285). The proband's mother, who was heterozygous for this variant, as well as the proband's sister, who was heterozygous for c.1437_1439del variant, were unaffected with polyps and colorectal cancer. This variant was also observed in homozygosity in three siblings in a different family (PMID: 20628285). Their heterozygous mother, father, and one sibling were unaffected with polyps and colorectal cancer (PMID: 20628285). This variant has been identified in 2/251048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2024	The c.504+19_504+31del13 intronic pathogenic mutation is located 19 nucleotides after coding exon 6 in the MUTYH gene. This variant results from a deletion of 13 nucleotides at positions c.504+19 to c.504+31. This variant has been reported in the homozygous state as well as in conjunction with MUTYH pathogenic mutations in individuals with adenomatous polyposis and co-segregated with disease in three affected siblings of a family (Di Gregorio C et al. Gastroenterology, 2006 Aug;131:439-44; Jones N et al. Gastroenterology, 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10; Fostira F et al. Dis. Colon Rectum, 2010 Aug;53:1197-201; Papp J et al. Fam. Cancer, 2016 Jan;15:85-97). Analysis by RT-PCR using RNA from a patient homozygous for this variant and a compound heterozygous patient was reported to result in complete in-frame skipping of MUTYH coding exon 6 (Fostira F et al. Dis. Colon Rectum, 2010 Aug;53:1197-201). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on an internal structural analysis, deletion of MUTYH coding exon 6 would be structurally deleterious (Ambry internal data). These nucleotide positions are not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Colonic neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 21, 2021

Medullary Carcinoma EST= - PRO = - HER2 = - KI = - -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs781222233; hg19: chr1-45798558;