Submissions for variant NM_001048174.2(MUTYH):c.309G>A (p.Trp103Ter)

dbSNP: rs587781295

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128998	SCV000172893	pathogenic	Hereditary cancer-predisposing syndrome	2019-07-13	criteria provided, single submitter	clinical testing	The p.W131* pathogenic mutation (also known as c.393G>A), located in coding exon 5 of the MUTYH gene, results from a G to A substitution at nucleotide position 393. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. This pathogenic mutation was identified in a proband who underwent hereditary cancer multigene panel testing (LaDuca H et al. Genet. Med. 2014 Nov;16:830-7; LaDuca H et al. PLoS ONE 2017 Feb;12:e0170843). 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	RCV000521741	SCV000617564	pathogenic	not provided	2017-06-26	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MUTYH c.393G>A at the cDNA level and p.Trp131Ter (W131X) atthe protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon(TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual referred for clinical testing for inheritedcancer (LaDuca 2014). We consider it to be pathogenic
Color Diagnostics, LLC DBA Color Health	RCV000128998	SCV000690572	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 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 not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001068416	SCV000919792	likely pathogenic	Familial adenomatous polyposis 2	2017-09-15	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.393G>A (p.Trp131X) variant is a nonsense change that results in the loss of the ~419 amino acids of MUTYH protein (~75%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.508delG, p.Val170X; c.1147delC, p.Ala385fsX23; c.1227_1228dupGG, p.Glu410fsX43). One in silico tool predicts a damaging outcome for this variant. The variant is absent from the large control population datasets of ExAC and gnomAD (~25184 and 246196 chrs tested, respectively). This variant has been reported in at least one affected individuals via a published report (LaDuca_2014). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae	RCV001068416	SCV001233528	pathogenic	Familial adenomatous polyposis 2	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp131*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 140811). For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000128998	SCV002532286	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-03-04	criteria provided, single submitter	curation