Submissions for variant NM_001048174.2(MUTYH):c.310G>A (p.Val104Ile)

gnomAD frequency: 0.00001  dbSNP: rs763273196

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165052	SCV000215753	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-08	criteria provided, single submitter	clinical testing	The c.394G>A (p.V132I) alteration is located in exon 5 (coding exon 5) of the MUTYH gene. This alteration results from a G to A substitution at nucleotide position 394, causing the valine (V) at amino acid position 132 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466109	SCV000545738	uncertain significance	Familial adenomatous polyposis 2	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 132 of the MUTYH protein (p.Val132Ile). This variant is present in population databases (rs763273196, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 185604). 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. 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	RCV000165052	SCV000685626	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 132 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 1/251414 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731494	SCV000697695	uncertain significance	not specified	2021-09-14	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.394G>A (p.Val132Ile) results in a 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 4e-06 in 251414 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.394G>A has been reported in the literature in four individuals affected with different types of cancer in one family (Tsai_2019). These report does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Additionally, co-occurrences with another pathogenic variant have been reported (RAD51D exon 7-10 deletion), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590403	SCV001134477	uncertain significance	not provided	2024-05-13	criteria provided, single submitter	clinical testing	The MUTYH c.394G>A (p.Val132Ile) variant has been reported in the published literature in an individual with lung cancer (PMID: 26689913 (2015)). The frequency of this variant in the general population, 0.000004 (1/251414 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000590403	SCV001871353	uncertain significance	not provided	2021-08-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002478507	SCV002790174	uncertain significance	Familial adenomatous polyposis 2; Gastric cancer	2021-12-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000466109	SCV004198870	uncertain significance	Familial adenomatous polyposis 2	2024-01-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000466109	SCV004839816	uncertain significance	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 132 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 1/251414 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.