ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1214C>A (p.Ala405Asp) (rs369299948)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130546 SCV000185415 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-23 criteria provided, single submitter clinical testing The p.A419D variant (also known as c.1256C>A), located in coding exon 13 of the MUTYH gene, results from a C to A substitution at nucleotide position 1256. The alanine at codon 419 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration, called a variant of unknown significance, has been reported in an Irish individual with approximately 12 colon polyps detected under the age of 50, and this individual was also found to carry another MUTYH variant of unknown significance (c.-2C>G) (McVeigh TP et al. Ir Med J, 2016 Dec;109:485). In another study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum. Genet., 2018 Oct;137:795-806). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000408991 SCV000487363 uncertain significance MYH-associated polyposis 2016-06-08 criteria provided, single submitter clinical testing
Invitae RCV000408991 SCV000639261 uncertain significance MYH-associated polyposis 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 419 of the MUTYH protein (p.Ala419Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs369299948, ExAC 0.01%). This variant has been observed in an individual affected with several polyps (PMID: 28644590). ClinVar contains an entry for this variant (Variation ID: 141858). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759155 SCV000888301 uncertain significance not provided 2019-07-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130546 SCV000911193 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-14 criteria provided, single submitter clinical testing This missense variant replaces alanine with aspartic acid at codon 419 of the MUTYH protein. This variant is also known as c.1214C>A (p.Ala405Lys) based on an alternative transcript (NM_001048171). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 8/282514 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.
GeneDx RCV000759155 SCV001777928 uncertain significance not provided 2020-02-03 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal polyps (McVeigh 2016); This variant is associated with the following publications: (PMID: 26580448, 28644590)

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