ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.797C>G (p.Ala266Gly) (rs750344996)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166396 SCV000217188 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-11 criteria provided, single submitter clinical testing The p.A266G variant (also known as c.797C>G), located in coding exon 10 of the MUTYH gene, results from a C to G substitution at nucleotide position 797. The alanine at codon 266 is replaced by glycine, an amino acid with similar properties. This alteration was reported as a variant of unknown signifcance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly 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.
Color Health, Inc RCV000166396 SCV000685671 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-17 criteria provided, single submitter clinical testing This missense variant replaces alanine with glycine at codon 266 of the MUTYH protein. 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 been reported in unknown phase with p.Glu466del in an individual affected with attenuated colorectal polyposis (https://databases.lovd.nl/shared/individuals/00203816) and in an individual undergoing evaluation for inherited cancer predisposition (PMID: 31159747). This variant has been identified in 2/249976 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.
GeneKor MSA RCV000166396 SCV000822079 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000698428 SCV000827089 uncertain significance MYH-associated polyposis 2020-08-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 266 of the MUTYH protein (p.Ala266Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs750344996, ExAC 0.002%). This variant has been observed in individual(s) who underwent genetic testing for personal or family history of cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 186750). 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 disruptive, 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.

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