Submissions for variant NM_001048174.2(MUTYH):c.49del (p.Ala17fs)

gnomAD frequency: 0.00002  dbSNP: rs587781704

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129874	SCV000184691	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-19	criteria provided, single submitter	clinical testing	The c.91delG pathogenic mutation, located in coding exon 2 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 91, causing a translational frameshift with a predicted alternate stop codon (p.A31Pfs*27). This mutation has been detected as homozygous or as compound heterozygous in patients affected with polyposis (>10 polyps) (Inra JA et al. Genet. Med. 2015 Oct;17(10):815-21). 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	RCV000479390	SCV000565908	pathogenic	not provided	2024-09-11	criteria provided, single submitter	clinical testing	Frameshift 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: 28152038, 30787465, 35668106, 32782288, 36735909, 25590978)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640397	SCV000761988	pathogenic	Familial adenomatous polyposis 2	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala31Profs*27) 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 (rs587781704, gnomAD 0.01%). 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: 141379). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479390	SCV000889535	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MUTYH mRNA and causes the premature termination of MUTYH protein synthesis. In the published literature, the variant has been reported in both the homozygous and compound heterozygous states in individuals with multiple polyps (PMID: 25590978 (2015)). In addition, it has been identified in an individual with renal cancer who was a carrier of this variant (PMID: 32782288 (2020)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129874	SCV001339706	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 2 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 5/251478 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000640397	SCV001361126	pathogenic	Familial adenomatous polyposis 2	2021-10-15	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.91delG (p.Ala31ProfsX27) 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 2e-05 in 251478 control chromosomes. c.91delG has been reported in the literature in multiple individuals affected with MUTYH-Associated Polyposis (Inra_2015). This variant was also identified in an individual with Renal Cancer and the individual was a carrier for this variant (Hartman_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000640397	SCV004198859	pathogenic	Familial adenomatous polyposis 2	2023-09-22	criteria provided, single submitter	clinical testing