Submissions for variant NM_001048174.2(MUTYH):c.1232T>C (p.Leu411Pro)

dbSNP: rs587780745

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123144	SCV000166447	uncertain significance	Familial adenomatous polyposis 2	2023-04-01	criteria provided, single submitter	clinical testing	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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 135984). This missense change has been observed in individual(s) with clinical features of MUTYH-related polyposis (PMID: 21520333; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs587780745, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 439 of the MUTYH protein (p.Leu439Pro).
GeneDx	RCV000484790	SCV000566313	uncertain significance	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in both cases and controls in a case-control study of hereditary breast cancer (Dorling et al. 2021); This variant is associated with the following publications: (PMID: 23108399, 33471991)
Ambry Genetics	RCV001010938	SCV001171203	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-13	criteria provided, single submitter	clinical testing	The p.L439P variant (also known as c.1316T>C), located in coding exon 13 of the MUTYH gene, results from a T to C substitution at nucleotide position 1316. The leucine at codon 439 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4	RCV001010938	SCV002532227	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-13	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484790	SCV004222073	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an affected individual with breast cancer as well as in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV000123144	SCV005056085	uncertain significance	Familial adenomatous polyposis 2	2023-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689617	SCV005185985	uncertain significance	not specified	2024-05-02	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1316T>C (p.Leu439Pro) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1316T>C has been reported in the literature in an individual affected with Breast Cancer (Akcay_2020). 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. The following publication have been ascertained in the context of this evaluation (PMID: 32658311). ClinVar contains an entry for this variant (Variation ID: 135984). Based on the evidence outlined above, the variant was classified as uncertain significance.