ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.929C>T (p.Ser310Leu) (rs558173961)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766300 SCV000211415 uncertain significance not provided 2018-06-25 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.971C>T at the cDNA level, p.Ser324Leu (S324L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MUTYH Ser324Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). MUTYH Ser324Leu is located in the 9-1-1 binding domain (Shi 2006, Luncsford 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MUTYH Ser324Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Ambry Genetics RCV000213585 SCV000276117 likely benign Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing in silico models in agreement (benign);Other strong data;Other strong data supporting benign classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000766300 SCV000601666 uncertain significance not provided 2020-02-21 criteria provided, single submitter clinical testing
Invitae RCV000552627 SCV000639368 uncertain significance MYH-associated polyposis 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 324 of the MUTYH protein (p.Ser324Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs558173961, ExAC 0.01%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 182695). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000552627 SCV000797228 uncertain significance MYH-associated polyposis 2018-01-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000213585 SCV000905859 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 324 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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 3/251458 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.
Mendelics RCV000552627 SCV001135256 likely benign MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing

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