Submissions for variant NM_001048174.2(MUTYH):c.928C>T (p.Gln310Ter)

gnomAD frequency: 0.00004  dbSNP: rs587780082

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212713	SCV000149662	pathogenic	not provided	2022-10-27	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; Observed with a pathogenic variant on the opposite allele (in trans) in individuals with colorectal cancer and/or polyps the published literature (Sampson et al., 2003; Aretz et al., 2006; Bouguen et al., 2007; Cattaneo et al., 2008; Vogt et al., 2009; Ricci et al., 2017); Published functional studies demonstrate a damaging effect: severely defective DNA glycosylase activity (Goto et al., 2010); Also known as c.970C>T p.(Gln324Ter) and c.928C>T p.(Gln310Ter); This variant is associated with the following publications: (PMID: 12853198, 25525159, 19032956, 31589614, 16557584, 17674103, 18091433, 19732775, 27829682, 26556299, 31203172, 20848659)
Ambry Genetics	RCV000115753	SCV000216400	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-31	criteria provided, single submitter	clinical testing	The p.Q338* pathogenic mutation (also known as c.1012C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1012. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been described in several individuals with attenuated polyposis and/or colon cancer (Sampson JR et al. Lancet. 2003 Jul;362:39-41; Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14; Olschwang S et al. Genet. Test. 2007;11:315-20; Bouguen G et al. Dis. Colon Rectum. 2007 Oct;50:1612-7; Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Guarinos C et al. Clin. Cancer Res. 2014 Mar;20:1158-68). The glycosylation function of the p.Q338* mutant MUTYH was classified as extremely impaired in one study measuring DNA glycosylase activity on adenine mispaired with 8-hydroxyguanine (Goto M et al. Hum. Mutat. 2010 Nov;31:E1861-74). Of note, p.Q338* has also been referred to as p.Q324X and p.Q310* in the 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465024	SCV000545804	pathogenic	Familial adenomatous polyposis 2	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln338*) 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 (rs587780082, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (MAP) (PMID: 2084865, 12853198, 16557584, 19732775, 24470512). This variant is also known as Q310X and Q324X. ClinVar contains an entry for this variant (Variation ID: 127835). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115753	SCV000685534	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-14	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. A functional study reported that this variant was severely defective for DNA glycosylase activity (PMID: 20848659). This variant has been reported in individuals affected with MUTYH-associated polyposis (PMID: 12853198, 16557584, 17674103, 17949294, 19032956, 19394335, 19732775, 24470512, 26556299, 27829682, 34704405). This variant has been identified in 20/263922 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.
CSER _CC_NCGL, University of Washington	RCV000465024	SCV000700131	pathogenic	Familial adenomatous polyposis 2	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 53 year old male diagnosed with colon cancer at age 47. Patient is compound heterozygous for a second pathogenic variant in MUTYH. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
PreventionGenetics, part of Exact Sciences	RCV000212713	SCV000806334	pathogenic	not provided	2016-12-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000465024	SCV001361132	pathogenic	Familial adenomatous polyposis 2	2019-07-10	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1012C>T (p.Gln338X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.2e-05 in 232530 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (8.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1012C>T has been reported in the literature in multiple individuals affected with MUTYH-associated Polyposis (Sampson_2003, Vogt_2009, Ricci_2017). These data indicate that the variant is very likely to be associated with disease. A functional study, GOTO_2010 reports the variant severely impairs adenine DNA glycosylase activity. Six ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000212713	SCV001500819	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498495	SCV002810552	pathogenic	Familial adenomatous polyposis 2; Gastric cancer	2021-11-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000465024	SCV004198822	pathogenic	Familial adenomatous polyposis 2	2023-12-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000465024	SCV004835137	pathogenic	Familial adenomatous polyposis 2	2023-12-18	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. A functional study reported that this variant was severely defective for DNA glycosylase activity (PMID: 20848659). To our knowledge, this variant has been reported in individuals affected with MUTYH-associated polyposis (PMID: 12853198, 16557584, 17674103, 17949294, 19032956, 19394335, 19732775, 24470512, 26556299, 27829682). This variant has been identified in 20/263922 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212713	SCV000592706	pathogenic	not provided		no assertion criteria provided	clinical testing