ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast or other cancers (PMID: 27720647, 25186627); This variant is associated with the following publications: (PMID: 23108399, 25186627, 27720647)

The frequency of this variant in the general population, 0.00076 (27/35360 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

This missense variant replaces serine with tyrosine at codon 6 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 27/280764 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.

Variant summary: MUTYH c.17C>A (p.Ser6Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 249362 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing Hereditary Breast And Ovarian Cancer Syndrome (9.6e-05 vs 0.0056), allowing no conclusion about variant significance. c.17C>A has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Tung_2014) or unspecified individual(s) undertaking cancel panel testing (Mu_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome or other MUTYH-related diseases. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27720647, 25186627). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces serine with tyrosine at codon 6 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 27/280764 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.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 6 of the MUTYH protein (p.Ser6Tyr). This variant is present in population databases (rs587782837, gnomAD 0.08%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 142941). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

The MUTYH c.17C>A variant is predicted to result in the amino acid substitution p.Ser6Tyr. This variant was observed in at least one individual who had a hereditary cancer panel performed; however no information was provided to support its pathogenicity (Mu et al. 2016. PubMed ID: 27720647, Supplementary Table 3). This variant is reported in 0.076% of alleles in individuals of Latino descent in gnomAD and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/142941/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.