ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1351C>G (p.Pro451Ala) (rs375597447)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130637 SCV000185516 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing The p.P465A variant (also known as c.1393C>G), located in coding exon 14 of the MUTYH gene, results from a C to G substitution at nucleotide position 1393. The proline at codon 465 is replaced by alanine, an amino acid with highly similar properties. This alteration was reported as a variant of uncertain significance identified in a cohort of 1058 colorectal cancer patients who underwent multi-gene panel testing and were unselected for age of diagnosis, family history, or MSI/MMR status (Yurgelun MB et al J. Clin. Oncol. 2017 Apr;35:1086-1095). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000229106 SCV000285926 uncertain significance MYH-associated polyposis 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 465 of the MUTYH protein (p.Pro465Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs375597447, ExAC 0.02%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant is also known as c.1351C>G (p.P451A) in the literature. ClinVar contains an entry for this variant (Variation ID: 141925). 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.
GeneDx RCV000657068 SCV000293201 uncertain significance not provided 2021-02-18 criteria provided, single submitter clinical testing Reported in the heterozygous state in individuals with colorectal cancer or polyposis; however, a pathogenic duplication in SCG5/GREM1 was also identified in the polyposis case (Ziai 2016, Yurgelun 2017) In silico analysis supports that this missense variant does not alter protein structure/function Not observed at a significant frequency in large population cohorts (Lek 2016) Also known as p.Pro451Ala This variant is associated with the following publications: (PMID: 26947005, 28135145)
Counsyl RCV000229106 SCV000487381 uncertain significance MYH-associated polyposis 2016-09-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130637 SCV000685570 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-18 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761015 SCV000890930 uncertain significance Retinoblastoma 2016-03-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235231 SCV001361129 uncertain significance not specified 2019-07-15 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1393C>G (p.Pro465Ala) results in a non-conservative amino acid change located in the MutY, C-terminal domain (IPR029119) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.8e-05 vs 0.0046), allowing no conclusion about variant significance. c.1393C>G has been reported in the literature in individuals affected with colorectal cancer and/or polyposis (Ziai_2016, Yurgelun_2017). In one of these reports this MUTYH variant was not the cause of disease as a different pathogenic variant, namely a 40 kb duplication upstream of the GREM1 gene segregated with the hereditary mixed polyposis syndrome (HMPS) phenotype (Ziai_2016). These report(s) 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353621 SCV000592716 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Pro465Ala variant was not identified in the literature, nor was it identified in dbSNP, HGMD, “InSiGHT Colon Cancer Database”, or the COSMIC database. The variant was identified in the NHLBI Exome Sequencing Project, with a frequency of 0.0001 in European American alleles; however, this frequency is based on one occurrence of the variant allele in 8600 alleles tested. The p.Pro465 residue is conserved in mammals but not across lower organisms, and the variant amino acid Alanine (Ala) is present in chicken, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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