ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.637G>A (p.Ala213Thr) (rs369854269)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222437 SCV000273111 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-26 criteria provided, single submitter clinical testing The p.A227T variant (also known as c.679G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 679. The alanine at codon 227 is replaced by threonine, an amino acid with similar properties. This amino acid position is 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.
Invitae RCV000460674 SCV000545723 uncertain significance MYH-associated polyposis 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 227 of the MUTYH protein (p.Ala227Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs369854269, ExAC 0.01%). This variant has been observed in individuals with breast cancer (PMID: 31159747, 26689913). ClinVar contains an entry for this variant (Variation ID: 229778). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
GeneDx RCV000589976 SCV000566119 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.679G>A at the cDNA level, p.Ala227Thr (A227T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has been identified in at least one individual with breast cancer (Lu 2015), as well as in one individual with schizophrenia but was also observed in one control subject, with no specific information about cancer history provided (Purcell 2014). MUTYH Ala227Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYH Ala227Thr occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MUTYH Ala227Thr is a pathogenic or benign variant. 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.
Color Health, Inc RCV000222437 SCV000685656 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-12 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 227 of the MUTYH protein. This variant is also known as c.637G>A (p.Ala213Thr) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been observed in individuals affected with MUTYH-associated polyposis in the literature. This variant has been identified in 9/251330 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 RCV001175349 SCV000697706 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: MUTYH c.679G>A (p.Ala227Thr) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251330 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.679G>A has been reported in the literature in a cohort of individuals undergoing testing for genes implicated in hereditary cancer predisposition (Tsaousis_2019)and also as a somatic variant (vandeWetering_2015). These reports do 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 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000460674 SCV000792955 uncertain significance MYH-associated polyposis 2017-08-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000589976 SCV000806365 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing
GeneKor MSA RCV000222437 SCV000822078 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000460674 SCV001257407 uncertain significance MYH-associated polyposis 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.

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