ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1434+2C>T (rs140288388)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166725 SCV000217536 benign Hereditary cancer-predisposing syndrome 2019-10-11 criteria provided, single submitter clinical testing Sub-population frequency in support of benign classification (not ava blue, manual h-w)
Invitae RCV000470920 SCV000545716 uncertain significance MYH-associated polyposis 2020-10-21 criteria provided, single submitter clinical testing This sequence change falls in a donor splice site in intron 14 of the MUTYH gene. This change appears to restore this site to a stronger consensus splice site (GT) than is found in the reference genome (GC). This variant is present in population databases (rs140288388, ExAC 0.1%). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 187040). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is likely to preserve normal RNA splicing, thereby not affecting the integrity of the wild-type MUTYH protein. However, this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506630 SCV000601636 uncertain significance not specified 2017-05-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166725 SCV000685586 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter clinical testing This variant causes a C to T nucleotide substitution at the +2 position of intron 14 of the MUTYH gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 37/282888 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000506630 SCV000697679 uncertain significance not specified 2021-07-18 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1476+2C>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 5/5 computational tools predict that this variant strengthens the canonical 5' splicing donor site (i.e. it seems to change a non-classical splice site into a classic, consensus splice site), therefore no significant impact on normal splicing is expected. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251488 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.0012 in the gnomAD database. This frequency is not higher than the expected maximum for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.0046), allowing no conclusion about variant significance. c.1476+2C>T has been reported in the literature as a VUS in 2 individuals affected with breast cancer undergoing multigene panel testing (example, Tung_2014). This report does not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=6), or benign (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as Variant of Uncertain Significance (VUS).
Counsyl RCV000470920 SCV000797044 uncertain significance MYH-associated polyposis 2018-01-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000470920 SCV000914411 uncertain significance MYH-associated polyposis 2017-05-28 criteria provided, single submitter clinical testing The MUTYH c.1434+2C>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL 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 for this variant, it 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 and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for MYH-associated polyposis.
Mendelics RCV000470920 SCV001135248 uncertain significance MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV001358548 SCV001866249 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358548 SCV001554315 uncertain significance not provided no assertion criteria provided clinical testing

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