Submissions for variant NM_001048174.2(MUTYH):c.131C>T (p.Pro44Leu)

gnomAD frequency: 0.00001  dbSNP: rs759140181

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219858	SCV000277441	likely benign	Hereditary cancer-predisposing syndrome	2023-12-27	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699386	SCV000828092	uncertain significance	Familial adenomatous polyposis 2	2024-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 72 of the MUTYH protein (p.Pro72Leu). This variant is present in population databases (rs759140181, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 233129). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV000219858	SCV000911828	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 72 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 reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 5/282650 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.
GeneDx	RCV001813772	SCV002061070	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with kidney cancer or with a personal and/or family history of breast or ovarian cancer (Yadav et al., 2017; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 27878467, 29684080)
Baylor Genetics	RCV000699386	SCV004198911	uncertain significance	Familial adenomatous polyposis 2	2023-08-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000699386	SCV004838098	uncertain significance	Familial adenomatous polyposis 2	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 72 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 reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 5/282650 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.