Submissions for variant NM_001048174.2(MUTYH):c.640G>T (p.Val214Leu)

gnomAD frequency: 0.00010  dbSNP: rs769766446

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164890	SCV000215576	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.V242L variant (also known as c.724G>T), located in coding exon 9 of the MUTYH gene, results from a G to T substitution at nucleotide position 724. The valine at codon 242 is replaced by leucine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). In another study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204713	SCV000262217	uncertain significance	Familial adenomatous polyposis 2	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 242 of the MUTYH protein (p.Val242Leu). This variant is present in population databases (rs769766446, gnomAD 0.006%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 185462). 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.
GeneDx	RCV000480213	SCV000565258	uncertain significance	not provided	2018-08-28	criteria provided, single submitter	clinical testing	This variant is denoted MUTYH c.724G>T at the cDNA level, p.Val242Leu (V242L) at the protein level, and results in the change of a Valine to a Leucine (GTG>TTG). MUTYH Val242Leu has been observed in at least one individual with Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). MUTYH Val242Leu was observed at an allele frequency of 0.01% (7/126198) in individuals of European ancestry in large population cohorts (Lek 2016). Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. MUTYH Val242Leu is located in the MSH6 binding domain (Gu 2002, Ruggieri 2013). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Val242Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Color Diagnostics, LLC DBA Color Health	RCV000164890	SCV000685664	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 242 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 suspected Lynch syndrome (PMID 25980754). In a meta-analysis, this variant was reported in 6/60466 breast cancer cases and 2/53461 controls (PMID: 33471991). This variant has been identified in 8/281824 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 Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000480213	SCV002011056	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797650	SCV002041621	uncertain significance	not specified	2021-11-18	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.724G>T (p.Val242Leu) 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 2e-05 in 250450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.724G>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals undergoing Lynch syndrome testing (example, Yurgelun_2015), affected with Breast Cancer and in unaffected controls (example, Dorling_2021). These reports 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000164890	SCV002532324	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-09	criteria provided, single submitter	curation
Baylor Genetics	RCV000204713	SCV004198798	uncertain significance	Familial adenomatous polyposis 2	2023-10-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000204713	SCV004839217	uncertain significance	Familial adenomatous polyposis 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 242 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 suspected Lynch syndrome (PMID 25980754). In a meta-analysis, this variant was reported in 6/60466 breast cancer cases and 2/53461 controls (PMID: 33471991). This variant has been identified in 8/281824 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.