ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.850-2A>G

gnomAD frequency: 0.00035  dbSNP: rs77542170
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000034683 SCV000166463 likely benign MUTYH-related attenuated familial adenomatous polyposis 2021-12-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129053 SCV000183748 likely benign Hereditary cancer-predisposing syndrome 2019-03-29 criteria provided, single submitter clinical testing Other data supporting benign classification;Sub-population frequency in support of benign classification (not ava blue, manual h-w)
GeneDx RCV000212712 SCV000211414 uncertain significance not provided 2021-06-09 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: aberrant mRNA splicing resulting in truncated protein, non-nuclear localization, and insufficient ability of homozygous cell line to repair DNA damage from oxidative stress compared to wild type cell lines in vitro (Tao 2004, Taki 2015, Chan 2020); Also known as c.892-2A>G; This variant is associated with the following publications: (PMID: 26436112, 19725997, 22865608, 17703316, 21134075, 24733792, 19506731, 19931546, 19479711, 28495237, 31360874, 25525159, 26296696, 27077130, 24620956, 15890374, 23605219, 18271935, 26684191, 24728327, 24799981, 22641385, 16890597, 22703879, 27600092, 24289550, 19793575, 22744763, 16081110, 21443744, 15180946, 26824983, 28195393, 25856671, 26902849, 26332594, 28166811, 28445943, 29030401, 29093764, 28526081, 28188963, 28332257, 29105096, 28706299, 29330641, 30093976, 28944238, 29431110, 31031852, 30886832, 30719162, 31062380, 30604180, 30833417, 30833958, 31575519, 32068069, 32255556, 32904697, 33024574, 34093829, 33313162, 24377541, 26689913, 33258288, 30982232)
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000122431 SCV000221200 uncertain significance not specified 2020-07-01 criteria provided, single submitter clinical testing The c.934-2A>G variant in MUTYH has been widely studied in the East Asian population and reported in at least 7 individuals with colorectal cancer; however, to our knowledge, none of these individuals had a second pathogenic germline MUTYH variant identified (Miyaki 2005 PMID:15890374, Kim 2007 PMID:17703316, Taki 2016 PMID:26684191). It has been identified in 1.54% (307/19952) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, This variant has also been reported in ClinVar (Variation ID 41766). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Functional studies was demonstrated to cause aberrant splicing in in vitro studies (Tao 2004 PMID:15180946, Taki 2016 PMID:26684191), but whether this alteration causes a biological loss of function of the MUTYH protein in humans is uncertain. In summary, while the predicted functional impact of this variant and in vitro studies favor a pathogenic role, based on the absence of reported affected individuals carrying this variant and a second pathogenic MUTYH variant in the literature despite its high frequency in the general population, its clinical significance is uncertain. Additional studies are needed to clarify the significance of this variant. ACMG/AMP Criteria applied: BS1_Supporting.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000034683 SCV000267403 pathogenic MUTYH-related attenuated familial adenomatous polyposis 2016-03-18 criteria provided, single submitter reference population
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212712 SCV000601664 uncertain significance not provided 2021-04-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000122431 SCV000697717 uncertain significance not specified 2022-02-03 criteria provided, single submitter clinical testing Variant summary: MUTYH c.934-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. At least three publications report experimental evidence that this variant affects mRNA splicing (Tao_2004, Taki_2016, Thibodeau_2019). However, one clinical laboratory reported RNA studies supporting a benign effect of this variant without providing original experimental data (Clinvar database). The variant allele was found at a frequency of 0.0012 in 253188 control chromosomes, predominantly at a frequency of 0.015 within the East Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis phenotype (0.0046). In addition, this variant was found in two Japanese control databases, jMorp and HGVD-Kyoto, with allele frequencies of 0.0205 and 0.0248, respectively. These data suggest that this variant is a benign polymorphism found primarily in populations of East Asian origin. c.934-2A>G has been reported in the literature in sequencing studies of multiple individuals affected with colorectal polyposis, HBOC, gallbladder, colon, endometrial and thyroid cancer (e.g. Miyaki_2005, Kim_2007, Frey_2015, Hirotsu_2015, Taki_2016, Hansen_2017, Li_2017, Zhang_2017, Chan_2018, Thibodeau_2019, Wang_2019, Slavin_2020). A publication (Jian_2017) reports two independent affected breast cancer patients who do not carry the variant of interest, while some of their unaffected daughters (younger than the average age of onset for breast cancer, 50 years) carried the variant. Case-control studies indicate that this variant may be associated with moderate increase in risk for colorectal cancer (Tao_2008, Yang_2013). None of the reported individuals with colorectal polyposis were indicated to be compound heterozygotes or homozygotes for MUTYH mutations. A recent case-control study in the Japanese population identified the variant in high frequency in both, controls and CRC cases, with homozygous CRC patients (4 cases) not exhibiting multiple polyps indicating per the authors that the variant should be assigned as benign (Fujita_2020). Additional studies detected homozygous occurrences of the variant in a patient diagnosed with gastric cancer and a patient with endometrial cancer without strong evidence of causality (Tao_2004, Wang_2019). All in all, none of these reports provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. Several co-occurrences with pathogenic variants have been reported in patients with associated penetrant phenotypes of Familial Adenomatous polyposis, breast and colorectal cancer [APC c.2751delT, p.D917fs (Kohda_2016); BRCA1 c.2110_2111delAA, p.N704CfsX7 (Yang_2015); APC with an unspecified deletion (Li_2017); BRCA2 c.774_775delAA, p.Glu260Serfs*15 (Chan_2018); MLH1 c.704_723del, p.Lys236Glufs*64 (Chan_2018)]. To our knowledge, no experimental evidence reporting an impact of this variant on the base excision repair activity of MUTYH has been reported. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=5, uncertain significance n=5, likely benign n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000034683 SCV000837758 likely pathogenic MUTYH-related attenuated familial adenomatous polyposis 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129053 SCV000910559 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-10 criteria provided, single submitter clinical testing This variant causes an A>G nucleotide substitution at the -2 position of intron 10 splice acceptor site of the MUTYH gene. This variant is also known as IVS10-2A>G in the literature and c.892-2A>G for an alternative MUTYH transcript (NM_001048171). RNA studies have shown that this variant can cause retention of intron 10, potentially resulting in a frameshift and premature translation stop signal (PMID: 15180946, 26684191) or use of a cryptic site resulting in a 9 nucelotide, in-frame deletion of exon 11. A functional study has reported that the mutant protein is mislocalized in the cell (PMID: 15180946). While these experimental studies suggest a deleterious effect of this variant, clinical observations do not clearly indicate a significant role in disease. The variant has been reported in many individuals affected with colorectal cancer (PMID: 15890374, 18271935, 22641385, 24377541, 24799981, 26684191, 26837502, 28195393, 28445943, 29330641, 31360874), colorectal polyposis (PMID: 17703316, 29330641, 33024574), breast and/or ovarian cancer (PMID: 24733792, 26436112, 26824983, 30833417, 30093976, 30982232, 32068069), and gastric cancer (PMID: 15180946, 29431110). However, the affected carriers were predominantly heterozygous for this variant, rather than homozygous or compound heterozygous as expected for autosomal recessive mode of inheritance for the MUTYH-associated polyposis and colorectal cancer. This variant has also been identified in 312/282820 chromosomes (307/19952 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD), including 5 East Asian homozygotes from the non-cancer cohort. Small colorectal cancer case-control studies have reported conflicting conclusions about this variant's association with disease (PMID: 18271935, 24377541). Given the observation of this variant in heterozygous affected individuals and healthy homozygous individuals, and the lack of definitive disease-association findings, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services,Illumina RCV000034683 SCV001255470 likely benign MUTYH-related attenuated familial adenomatous polyposis 2017-04-27 criteria provided, single submitter clinical testing 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Division of Medical Genetics, University of Washington RCV000034683 SCV001424787 uncertain significance MUTYH-related attenuated familial adenomatous polyposis 2019-01-03 criteria provided, single submitter clinical testing The c.934-2A>G variant is predicted to lead to either nonsense-mediated mRNA decay or an abnormal protein product by destroying a canonical splice acceptor site. In vitro studies of this variant have demonstrated aberrant splicing and that the variant protein, if translated, is not localized to the nucleus (Tao 2004, Taki 2016). The c.934-2A>G variant was identified in 1.6% of East Asian chromosomes in the Genome Aggregation Database ( This variant has been reported in the literature in a heterozygous state in multiple individuals with colorectal cancer; however has never, to our knowledge, been reported in an affected individual that is homozygous or compound heterozygous for a second MUTYH pathogenic variant (Miyaki 2005, Kim 2007, Taki 2016).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212712 SCV001474441 uncertain significance not provided 2021-07-04 criteria provided, single submitter clinical testing The MUTYH c.934-2A>G variant (rs77542170), also known as IVS10-2A>G or c.892-2A>G for NM_001048171, is reported in the literature in multiple individuals with colorectal adenomatous polyposis or colorectal cancer, but has only been reported in the heterozygous state with no additional MUTYH variant identified (Hansen 2017, Taki 2016, Zhang 2017). This variant has also been reported heterozygously in individuals with breast and/or ovarian cancer (Hirotsu 2015, Kurian 2014) as well as an individual with glioma (Kline 2016). This variant is found heterozygously at a similar frequency in individuals with gastric cancer as in controls (Tao 2004). This variant disrupts the canonical splice acceptor site of intron 10, and RNA analysis shows this alters splicing and causes intron 10 retention leading to a premature termination codon; however the proportion of aberrant transcripts compared to wild type is unclear (Tao 2004). This variant is also reported in the ClinVar database (Variation ID: 41766) and is found in the East Asian population with an allele frequency of 1.5% (307/19952 alleles, including 5 homozygotes) in the Genome Aggregation Database, which is greater than expected for a pathogenic variant. Due to conflicting information, the clinical significance of the c.934-2A>G variant is uncertain at this time.
Baylor Genetics RCV000034683 SCV001481723 uncertain significance MUTYH-related attenuated familial adenomatous polyposis 2020-12-04 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Baylor Genetics RCV001334797 SCV001527760 likely pathogenic Gastric cancer 2018-11-03 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has previously been reported as disease-causing [PMID 15180946, 22703879, 24733792, 24728327] With updated public general population genomic data and literatures, we now reclassified this variant as likely pathogenic [PMID 26332594, 26684149]
CeGaT Center for Human Genetics Tuebingen RCV000212712 SCV001961111 uncertain significance not provided 2021-08-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034683 SCV000043373 probably pathogenic MUTYH-related attenuated familial adenomatous polyposis 2012-07-13 no assertion criteria provided research Converted during submission to Likely pathogenic.
ITMI RCV000122431 SCV000083982 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357924 SCV001553529 likely pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH c.934-2A>G variant was identified in 19 of 2400 proband chromosomes and 1 homozygous proband at a frequency of 0.025 from East Asian (Japanese, Chinese and Korean) individuals with colorectal polyps and/or colorectal, gastric and breast cancers and was present in 21 of 1206 control chromosomes (frequency: 0.014) from healthy individuals (Tao 2004, Lin 2016, Zhang 2017, Miyaki 2005, Jang 2015, Johnston 2012, Taki 2016 and Kim 2007). The variant was also identified in the following databases: dbSNP (ID: rs77542170 as “With other allele”) and ClinVar (1x as pathogenic by Soonchunhyang University Bucheon Hospital; 4x as likely pathogenic by Invitae, GeneDx, Quest Diagnostics, and Biesecker Lab/NIH; and 3x as uncertain significance by Ambry Genetics, Laboratory for Molecular Medicine, and Integrated Genetics/Laboratory Corporation of America). The variant was not identified in the Cosmic, MutDB or UMD-LSDB databases. The variant was identified in control databases in 298 of 277146 chromosomes (5 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 293 of 18870 chromosomes (5 homozygous, freq: 0.015), and South Asian in 5 of 30782 chromosomes (freq: 0.0002) and the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish or Finnish populations. The c.934-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence, and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. Two independent studies have shown the MUTYH c.934-2A>G variant results in an aberrant mRNA transcript which retains intron 10, has a premature stop codon in exon 11, and encodes a truncated protein (Tao 2004 and Taki 2015). Further, in vitro expression studies demonstrate that, if translated, the variant protein is not localized in the nucleus like the wild type protein, suggesting insufficient ability of the variant protein to repair nuclear DNA (Tao 2004). 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 pathogenic role for this variant. This variant is classified as likely pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000122431 SCV002547274 likely benign not specified no assertion criteria provided clinical testing

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