Submissions for variant NM_001048174.2(MUTYH):c.559G>A (p.Val187Met)

gnomAD frequency: 0.00001  dbSNP: rs776487884

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164298	SCV000214928	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.V215M variant (also known as c.643G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 643. The valine at codon 215 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in both a homozyous state and in conjunction with a likely pathogenic variant in MUTYH in individuals with polyposis (Ambry internal data). This alteration has also been reported in conjunction with a MUTYH pathogenic variant in an individual diagnosed at age 30 with colorectal cancer as well as numerous colorectal and duodenal adenomas and has a high probability of being in trans given it has co-occurred with multiple different mutations (Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000502295	SCV000639349	pathogenic	Familial adenomatous polyposis 2	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the MUTYH protein (p.Val215Met). This variant is present in population databases (rs776487884, gnomAD 0.03%). This missense change has been observed in individual(s) with MUTYH-associated polyposis syndrome (PMID: 19032956, 19732775, 20618354; Invitae; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 184952). 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. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164298	SCV000690595	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 215 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer with more than 100 colorectal polyps and a pathogenic MUTYH co-variant c.884C>T (p.Pro295Leu)(PMID: 20618354). This variant has also been identified in the compound heterozygous state in an individual affected with multiple adenomatous polyps and in the homozygous state in an individual affected with colon cancer and colorectal polyps (communication with an external laboratory; ClinVar SCV000214928.5). This variant has been identified in 12/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001358407	SCV002559784	likely pathogenic	not provided	2023-08-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19032956, 27014339, 19394335, 24834277, 28577310, 34426522, 19732775, 20618354)
Baylor Genetics	RCV000502295	SCV004198861	likely pathogenic	Familial adenomatous polyposis 2	2023-12-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001358407	SCV004222096	pathogenic	not provided	2022-10-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00029 (9/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with MUTYH associated polyposis co-occurring with an additional pathogenic MUTYH variant (PMID: 19032956 (2009), 19394335 (2009)). In a large breast cancer association study, the variant was reported in affected and unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/MUTYH). 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, this variant is classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV000502295	SCV004841648	likely pathogenic	Familial adenomatous polyposis 2	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 215 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer with more than 100 colorectal polyps and a pathogenic MUTYH co-variant c.884C>T (p.Pro295Leu)(PMID: 20618354). This variant has also been identified in the compound heterozygous state in an individual affected with multiple adenomatous polyps and in the homozygous state in an individual affected with colon cancer and colorectal polyps (communication with an external laboratory; ClinVar SCV000214928.5). This variant has been identified in 12/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358407	SCV001554131	pathogenic	not provided		no assertion criteria provided	clinical testing