Submissions for variant NM_001128425.2(MUTYH):c.200del (p.Gly67fs)

dbSNP: rs746449748

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479773	SCV000567734	pathogenic	not provided	2015-08-18	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MUTYH is denoted c.200delG at the cDNA level and p.Gly67AlafsX24 (G67AfsX24) at the protein level. The normal sequence, with the base that is deleted in braces, is GCAG[G]CCTG. The deletion causes a frameshift, which changes a Glycine to an Alanine at codon 67, and creates a premature stop codon at position 24 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.Although this variant is considered pathogenic, a second mutation, as would be required for expression of the recessive condition MAP, was not detected in this individual. The possibility that this patient harbors a second disease-causing MUTYH mutation that is undetectable by this test cannot be excluded. While a single variant in the MUTYH gene has been reported in association with a slightly increased risk for colon cancer, endometrial cancer, and breast cancer, particularly among those with a family history of colorectal cancer (Jenkins 2006, Win 2011, Rennert 2012), there are conflicting data regarding these associations (Santonocito 2011, Out 2012). MUTYH-associated polyposis (MAP) is an autosomal recessive condition caused by two mutations (one affecting each allele) in the MUTYH gene which results in an increased risk for the development of colon cancer and colon polyps. If a MUTYH mutation carrier'spartner is also heterozygous for a MUTYH mutation, the risk to have a child with MAP is 25% with each pregnancy. One study from the UK estimated the overall carrier frequency for any MUTYH mutation to be about 2% (Aretz 2010).
Ambry Genetics	RCV000493987	SCV000581683	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-16	criteria provided, single submitter	clinical testing	The c.200delG pathogenic mutation, located in coding exon 3 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 200, causing a translational frameshift with a predicted alternate stop codon (p.G67Afs*24). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000801139	SCV000917812	likely pathogenic	Familial adenomatous polyposis 2	2018-11-06	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.200delG (p.Gly67AlafsX24) 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 (eg. c.289C>T (p.Arg97X), c.312C>A (p.Tyr104X), and c.1147delC (p.Ala385fsX23)). The variant allele was found at a frequency of 1.6e-05 in 245776 control chromosomes (gnomAD). To our knowledge, no occurrence of c.200delG in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801139	SCV000940904	pathogenic	Familial adenomatous polyposis 2	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly67Alafs*24) 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 (rs746449748, gnomAD 0.004%). 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: 419735). 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.
Baylor Genetics	RCV000801139	SCV004198948	likely pathogenic	Familial adenomatous polyposis 2	2023-05-19	criteria provided, single submitter	clinical testing