ClinVar Genomic variation as it relates to human health

ACMG classification criteria: PS4 supporting, PM2 moderate

Variant summary: MUTYH c.481G>C (p.Asp161His) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of 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 0.0001 in 250434 control chromosomes, predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database. This frequency is not higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0001 vs 0.0046), allowing no conclusion about variant significance. c.481G>C has been reported in the literature in individuals affected prostate cancer (Chan_2018), suspected lynch syndrome (Yurgelun_2015) without strong evidence for causality. Variant has been reported in a patient with colorectal cancer and a second pathogenic allele p.Y179C (Pitroski_2011). Additionally, the variant has also been reported in breast cancer cases and controls (Dorling_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

The frequency of this variant in the general population, 0.00054 (19/35412 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer and/or polyposis (PMIDs: 25938944 (2015) and 25980754 (2015)), Cowden Syndrome (PMID: 29684080 (2018)), endometrial cancer (PMID: 27443514 (2016)), prostate cancer (PMID: 30093976 (2018)), breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)) and pediatric astrocytoma (PMID: 31970404 (2020)). Additionally, the variant has been reported in healthy individuals with no personal or family history of cancer (PMIDs: 21777424 (2011) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). 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 sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 161 of the MUTYH protein (p.Asp161His). This variant is present in population databases (rs564930066, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer, clinical features of MUTYH-associated polyposis (MAP), and/or endometrial cancer (PMID: 21424714, 25980754, 27443514, 30093976, 35264596; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 140814). 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 c.481G>C variant (also known as p.D161H), located in coding exon 6 of the MUTYH gene, results from a G to C substitution at nucleotide position 481. The aspartic acid at codon 161 is replaced by histidine, an amino acid with similar properties. This variant has been detected in conjunction with a MUTYH pathogenic variant or as homozygous in multiple unrelated individuals with clinical features of MUTYH-associated disease; however, the phase of the variants from the compound heterozygous cases is unknown (Ambry internal data). This variant was also reported in conjunction with MUTYH p.P405L in a patient with colorectal cancer (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). This alteration has also been reported in prostate and breast cancer cohorts who underwent hereditary multigene panel testing (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. However, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Co-observed with a MUTYH variant, phase unknown, in a patient with colorectal cancer and polyps (PMID: 25938944; personal communication with authors); Observed in heterozygous state in individuals with polyposis, breast cancer, astrocytoma, endometrial cancer, and prostate cancer (PMID: 30093976, 35264596, 35980532, 27443514, 31970404, 38254803); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21777424, 25980754, 29684080, 30093976, 33471991, 17161978, Giacomazzi2022[preprint], 35264596, 27443514, 21424714, 25938944, 38254803, 31970404, 35980532)

This missense variant replaces aspartic acid with histidine at codon 161 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three biallelic individuals affected with colorectal cancer and/or MUTYH-associated polyposis (PMID: 21424714, 25938944; ClinVar Accession: SCV000172897.8). This variant has also been detected in two individuals who were tested for Lynch syndrome (PMID: 25980754, 38060977), two individuals affected with endometrial cancer (PMID: 27443514), an individual affected with prostate cancer (PMID: 30093976), an individual affected with either Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 29684080), and several individuals affected with breast cancer (PMID: 35264596). In an international breast cancer case-control meta-analysis, this variant was detected in 5/60466 cases and 14/53461 unaffected controls (OR=0.316, 95%CI 0.114 to 0.877, p-value=0.022; PMID: 33471991). This variant has been identified in 29/281806 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.

The MUTYH c.481G>C variant is predicted to result in the amino acid substitution p.Asp161His. This variant was reported in individuals with suspected Lynch syndrome, kidney renal clear cell carcinoma, prostate cancer, or breast cancer (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table S7, Yehia et al. 2018. PubMed ID: 29684080; Table S2, Chan et al. 2018. PubMed ID: 30093976; Table S3, Guindalini et al. 2022. PubMed ID: 35264596). This variant was also reported along with an established pathogenic MUTYH variant in an individual with colorectal cancer (Pitroski et al. 2011. PubMed ID: 21424714). This variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45798613-C-G) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/140814). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.