Submissions for variant NM_001048174.2(MUTYH):c.420+19_420+31del

dbSNP: rs781222233

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459179	SCV000545720	pathogenic	Familial adenomatous polyposis 2	2023-07-24	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000580373	SCV000685635	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000459179	SCV000799495	likely pathogenic	Familial adenomatous polyposis 2	2018-04-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679429	SCV000806359	likely pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580373	SCV001185342	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-19	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679429	SCV002506259	pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000679429	SCV004123769	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	MUTYH: PM3:Strong, PM2, PS3:Supporting, PS4:Supporting
Baylor Genetics	RCV000459179	SCV004198977	pathogenic	Familial adenomatous polyposis 2	2023-03-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000459179	SCV004815007	likely pathogenic	Familial adenomatous polyposis 2	2023-06-26	criteria provided, single submitter	clinical testing	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000679429	SCV005187351	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001579292	SCV001805825	likely pathogenic	Colonic neoplasm	2021-08-21	no assertion criteria provided	clinical testing	Medullary Carcinoma EST= - PRO = - HER2 = - KI = -