Submissions for variant NM_001048174.2(MUTYH):c.1102+9A>T

gnomAD frequency: 0.00018  dbSNP: rs587780742

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123140	SCV000166442	likely benign	Familial adenomatous polyposis 2	2022-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129212	SCV000183962	likely benign	Hereditary cancer-predisposing syndrome	2015-09-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000123140	SCV000357893	uncertain significance	Familial adenomatous polyposis 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000123140	SCV000487386	likely benign	Familial adenomatous polyposis 2	2016-10-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000431410	SCV000513736	benign	not specified	2015-03-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics, PreventionGenetics	RCV000589767	SCV000806338	likely benign	not provided	2017-04-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129212	SCV000910733	likely benign	Hereditary cancer-predisposing syndrome	2016-06-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000123140	SCV001135252	likely benign	Familial adenomatous polyposis 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000431410	SCV001363474	uncertain significance	not specified	2019-11-08	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1186+9A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 249362 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.00021 vs 0.0046), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1186+9A>T in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=5) and as uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV000431410	SCV002066240	likely benign	not specified	2021-11-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000431410	SCV002552496	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000589767	SCV001925670	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000589767	SCV001963577	likely benign	not provided		no assertion criteria provided	clinical testing