Submissions for variant NM_001048174.2(MUTYH):c.1222C>G (p.Leu408Val)

gnomAD frequency: 0.00001  dbSNP: rs587782043

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130506	SCV000185375	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-19	criteria provided, single submitter	clinical testing	The p.L436V variant (also known as c.1306C>G), located in coding exon 13 of the MUTYH gene, results from a C to G substitution at nucleotide position 1306. The leucine at codon 436 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in 1/299 Italian individuals with suspected MUTYH-associated polyposis (MAP) (Ricci MT et al. J. Hum. Genet., 2017 Feb;62:309-315). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000412469	SCV000487374	uncertain significance	Familial adenomatous polyposis 2	2016-08-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130506	SCV000905852	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-19	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 436 of the MUTYH protein. This variant is also known as c.1264C>G (p.Leu422Val) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer and/or colon polyp (PMID: 27829682). This variant has been identified in 2/251378 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412469	SCV000963790	uncertain significance	Familial adenomatous polyposis 2	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 436 of the MUTYH protein (p.Leu436Val). This variant is present in population databases (rs587782043, gnomAD 0.002%). This missense change has been observed in individual(s) with MUTYH-associated polyposis (PMID: 27829682). ClinVar contains an entry for this variant (Variation ID: 141833). 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.
GeneDx	RCV001580457	SCV001817781	uncertain significance	not provided	2020-04-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with polyps (Ricci 2017); This variant is associated with the following publications: (PMID: 27829682)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001580457	SCV002774651	uncertain significance	not provided	2021-06-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000412469	SCV004831109	uncertain significance	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 436 of the MUTYH protein. This variant is also known as c.1264C>G (p.Leu422Val) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer and/or colon polyp (PMID: 27829682). This variant has been identified in 2/251378 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130506	SCV005045364	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-09	criteria provided, single submitter	clinical testing