Submissions for variant NM_001048174.2(MUTYH):c.1087C>T (p.Gln363Ter)

gnomAD frequency: 0.00001  dbSNP: rs587783057

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410310	SCV000487361	pathogenic	Familial adenomatous polyposis 2	2016-06-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000413062	SCV000490628	pathogenic	not provided	2024-04-09	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; Published functional studies demonstrate a damaging effect: severely defective glycosylase and DNA binding activities (PMID: 18534194); Not observed at significant frequency in large population cohorts (gnomAD); Also known as Gln377Ter; This variant is associated with the following publications: (PMID: 21061173, 27829682, 32980694, 34761457, 34637943, 25525159, 21171015, 19531215, 17949294, 22402879, 16140997, 27194394, 26202870, 19032956, 17219385, 19245865, 16557584, 19732775, 31207142, 34426522, 31589614, 30787465, 35418818, 36988593, 36555431, 34428338, 33309985, 35988656, 36243179, 18564191, 24444654, 34981295, 35261632, 37453313, 18534194)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410310	SCV000545766	pathogenic	Familial adenomatous polyposis 2	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln391*) 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 (rs587783057, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (PMID: 16140997, 19732775, 24444654). This variant is also known as c.1129C>T (p.Q377X). ClinVar contains an entry for this variant (Variation ID: 156509). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000569738	SCV000670131	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	clinical testing	The p.Q391* pathogenic mutation (also known as c.1171C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1171. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been previously described in several individuals with attenuated polyposis and/or colon cancer in homozygous state or in conjugation with another pathogenic mutation (Nielsen M et al. J. Med. Genet. 2005 42(9):e54; Croitoru M et al. J. Surg. Oncol. 2007; 95(6):499-506; Olschwang S et al. Genet. Test. 2007; 11(3):315-20; Jones N et al. Gastroenterology 2009; 137(2):489-94, 494.e1; Vogt S et al. Gastroenterology 2009; 137(6):1976-85.e1-10; Ricci MT et al. J. Hum. Genet., 2017 Feb;62:309-315; Aretz S et al. Int J Cancer 2006 Aug;119(4):807-14). In addition, this mutation is also designated as Q377X in published literature. 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.
Color Diagnostics, LLC DBA Color Health	RCV000569738	SCV000685548	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal polyposis and/or cancer in the homozygous or compound heterozygous state with another pathogenic variant (PMID: 16140997, 18564191, 19732775, 24444654, 27829682). This variant has been identified in 3/249660 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.
Mendelics	RCV000410310	SCV000837752	pathogenic	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000413062	SCV000888297	pathogenic	not provided	2017-11-24	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000569738	SCV001950432	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-09	criteria provided, single submitter	clinical testing
DASA	RCV002221498	SCV002498799	pathogenic	Familial colorectal cancer	2022-04-10	criteria provided, single submitter	clinical testing	The c.1171C>T;p.(Gln391*) variant creates a premature translational stop signal in the MUTYH gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 156509; PMID: 16140997; PMID: 19732775; PMID: 24444654; PMID: 18534194; PMID: 20663686; PMID: 16557584; PMID: 17219385) - PS4. The variant is present at low allele frequencies population databases (rs587783057 – gnomAD 0.0001202%; ABraOM no frequency - http://abraom.ib.usp.br) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic
Revvity Omics, Revvity	RCV000410310	SCV003820311	pathogenic	Familial adenomatous polyposis 2	2022-03-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000410310	SCV004198966	pathogenic	Familial adenomatous polyposis 2	2024-02-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413062	SCV005093262	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MUTYH: PVS1, PM2, PM3
Pathway Genomics	RCV000144635	SCV000189962	pathogenic	Carcinoma of colon	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000144635	SCV001553370	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Gln391X variant was identified in 4 of 1188 proband chromosomes (frequency: 0.003) from individuals or families with colorectal cancer (Jones 2009, Vogt 2009, Win 2011). The variant was also identified in dbSNP (ID: rs587783057) as With Pathogenic allele, ClinVar (classified as pathogenic by Counsyl, GeneDx, Invitae, Pathway Genomics), Clinvitae (classified as pathogenic by ClinVar, Invitae (alias c.1129C>T)), UMD-LSDB (22X causal), Insight Colon Cancer Gene Variant Database (classified as probably pathogenic), databases. The variant was not identified in Genesight-COGR, databases. The variant was identified in control databases in 4 of 245576 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include EuropeanNon-Finnish in 4 of 111460 chromosomes (freq: 0.000036), while the variant was not observed in the African, Other, Latino, AshkenaziJewish, EastAsian, EuropeanFinnish, and SouthAsian populations. The c.1171C>T variant leads to a premature stop codon at position 391 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001572626	SCV001792255	pathogenic	Breast carcinoma	2021-08-19	no assertion criteria provided	clinical testing	Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000413062	SCV001799792	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413062	SCV001955530	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162600	SCV002758515	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research