Submissions for variant NM_001048174.2(MUTYH):c.775del (p.Ala259fs)

dbSNP: rs761468459

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000777643	SCV000913514	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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 (also known as c.817del in the literature) has been reported in an individual affected with MUTYH-associated polyposis (PMID: 16557584). This variant has also been identified in 1/250896 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000499908	SCV000967776	likely pathogenic	Familial adenomatous polyposis 2	2018-09-06	criteria provided, single submitter	clinical testing	The p.Ala287ProfsX32 variant in MUTYH has been reported in the heterozygous stat e in one individuals with familial adenomatouspolyposis (Aretz 20016). It has al so been identified in 1/30782 of South Asian chromosomes by gnomAD (http://gnoma d.broadinstitute.org). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 287 and leads to a premature termination codon 32 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, although addition al studies are required to fully establish its clinical significance, the p.Ala2 87ProfsX32 variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.
Ambry Genetics	RCV000777643	SCV001179223	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The c.859delG variant, located in coding exon 10 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 859, causing a translational frameshift with a predicted alternate stop codon (p.A287Pfs*32). This variant (designated as MUTYH c.817delG p.A273PfsX32) has been reported in the heterozygous state in one individual with a clinical diagnosis of familial adenomatous polyposis (Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14). 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	RCV000499908	SCV001399526	pathogenic	Familial adenomatous polyposis 2	2023-01-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433934). This variant is also known as c.817delG, p.A273PfsX32. This premature translational stop signal has been observed in individual(s) with polyposis (PMID: 16557584). This variant is present in population databases (rs761468459, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ala287Profs*32) 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).
CeGaT Center for Human Genetics Tuebingen	RCV001310852	SCV001500820	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000777643	SCV002532336	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Human Genetics Bochum, Ruhr University Bochum	RCV000499908	SCV004042788	pathogenic	Familial adenomatous polyposis 2	2023-06-15	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP
Baylor Genetics	RCV000499908	SCV004199417	pathogenic	Familial adenomatous polyposis 2	2022-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001310852	SCV005202010	pathogenic	not provided	2023-11-25	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); Observed in the heterozygous state in an individual with a history of polyposis (PMID: 16557584); Also known as 817delG; This variant is associated with the following publications: (PMID: 16557584)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353713	SCV000592699	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Ala287ProfsX32 variant was identified in 1 of 658 proband chromosomes (frequency: 0.002) from individuals or families with MUTYH associated polyposis, and was not identified in 116 control chromosomes from healthy individuals (Aretz 2006). The p.Ala287ProfsX32 variant was also identified in HGMD and the “InSiGHT Colon Cancer Database”. The p.Ala287ProfsX32 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 287 and leads to a premature stop codon 32 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.