Submissions for variant NM_001048174.2(MUTYH):c.544C>T (p.Gln182Ter)

gnomAD frequency: 0.00001  dbSNP: rs376561094

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223123	SCV000277834	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-30	criteria provided, single submitter	clinical testing	The p.Q210* pathogenic mutation (also known as c.628C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide position 628. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration has been identified in conjunction with a second MUTYH mutation in individuals affected with MUTYH-associated polyposis (Aretz S et al. Int. J. Cancer 2006 Aug;119(4):807-14; Nielsen M et al. Gastroenterology 2009 Feb;136(2):471-6; Vogt S et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10). In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	RCV000426595	SCV000517268	pathogenic	not provided	2023-10-04	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); This variant is associated with the following publications: (PMID: 33471991, 16557584, 19032956, 19394335, 19725997, 17161978, 25525159, 26269718, 30787465, 30604180, 19732775)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554059	SCV000639348	pathogenic	Familial adenomatous polyposis 2	2023-09-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln210*) 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 (rs376561094, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis (PMID: 16557584, 19732775). This variant is also known as Q196X. ClinVar contains an entry for this variant (Variation ID: 233460). 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.
Color Diagnostics, LLC DBA Color Health	RCV000223123	SCV001351413	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 8 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 (MAP; PMID: 16557584, 19032956, 19732775). This variant has been identified in 1/251452 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.
CeGaT Center for Human Genetics Tuebingen	RCV000426595	SCV004704239	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MUTYH: PVS1, PM2
All of Us Research Program, National Institutes of Health	RCV000554059	SCV004841670	pathogenic	Familial adenomatous polyposis 2	2023-10-02	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 8 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 (MAP; PMID: 16557584, 19032956, 19732775). This variant has been identified in 1/251452 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.