Submissions for variant NM_001048174.2(MUTYH):c.655C>T (p.Arg219Ter)

gnomAD frequency: 0.00002  dbSNP: rs587782885

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132522	SCV000187619	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The p.R247* pathogenic mutation (also known as c.739C>T) located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 739. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been reported previously in multiple Dutch individuals with a diagnosis of MUTYH-associated polyposis (Nielsen M et al. J. Med. Genet. 2005 Sep;42:e54; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Nielsen M et al. BMC Cancer. 2009 Jun;9:184; van der Post RS et al. Virchows Arch. 2009 Jan;454:25-9). This alteration is also referred to as c.697C>T and p.R233X in the literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000236829	SCV000292768	pathogenic	not provided	2022-06-25	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.697C>T and R233X; This variant is associated with the following publications: (PMID: 25525159, 19032956, 16140997, 19394335, 19725997, 19031083, 28152038, 30604180, 19527492, 19732775)
Counsyl	RCV000500909	SCV000797054	pathogenic	Familial adenomatous polyposis 2	2018-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132522	SCV000905861	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 19732775, 19031083, 16140997, http://www.insight-database.org/). This variant has been identified in 1/249816 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 Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000500909	SCV000957992	pathogenic	Familial adenomatous polyposis 2	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg247*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs587782885, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (PMID: 16140997, 19732775). This variant is also known as p.Arg233X. ClinVar contains an entry for this variant (Variation ID: 143003). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000500909	SCV003820334	pathogenic	Familial adenomatous polyposis 2	2022-02-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000500909	SCV004198906	pathogenic	Familial adenomatous polyposis 2	2024-02-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000500909	SCV004839173	pathogenic	Familial adenomatous polyposis 2	2023-08-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 19732775, 19031083, 16140997, http://www.insight-database.org/). This variant has been identified in 1/249816 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 Pathogenic.
Pathway Genomics	RCV000144630	SCV000189957	likely pathogenic	Carcinoma of colon	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000144630	SCV000592697	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Arg247X variant is reported in the literature in 2 of 88 proband chromosomes of individuals with colorectal carcinomas from MUTYH-associated polyposis (MAP) families, both of whom were compound heterozygous for this variant, consistent with the autosomal recessive inheritance of MAP. However, no controls were tested to establish the frequency of the variant in the general population (Nielsen_2009). The variant leads to a premature stop codon at position 247 which is predicted to cause premature truncation of the protein product. This is a loss of function DNA variant and loss of function is an established disease mechanism for the MUTYH gene. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000236829	SCV001741005	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000236829	SCV001919082	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000236829	SCV001957362	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000236829	SCV001974424	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162593	SCV002758520	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research