Submissions for variant NM_001048174.2(MUTYH):c.386C>T (p.Pro129Leu)

gnomAD frequency: 0.00001  dbSNP: rs777184451

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165108	SCV000215818	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing	The p.P157L variant (also known as c.470C>T), located in coding exon 6 of the MUTYH gene, results from a C to T substitution at nucleotide position 470. The proline at codon 157 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in conjunction with a pathogenic MUTYH mutation in an individual with an attenuated polyposis phenotype; however, the phase (cis vs trans) of these two alterations was not determined (Aretz S et al. Int. J. Cancer 2006 Aug;119(4):807-14; Vogt S et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10). There is another report of this alteration being identified in an Italian individual with polyps at age 45 in conjunction with a different pathogenic MUTYH mutation (Ricci MT et al. J. Hum. Genet. 2017 Feb;62(2):309-315). This alteration has also been identified in our clinical laboratory in conjunction with pathogenic MUTYH mutations in individuals with adenomatous polyps, but the phase of these alterations was not determined (Ambry internal data). In a functional study, the ability of human MUTYH variant proteins to complement a Mut-deficient E. coli strain was measured and this variant demonstrated partially defective function; however, protein expression and subcellular localization were similar to wild type MUTYH (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000226581	SCV000285951	pathogenic	Familial adenomatous polyposis 2	2023-10-30	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 157 of the MUTYH protein (p.Pro157Leu). This variant is present in population databases (rs777184451, gnomAD 0.007%). This missense change has been observed in individual(s) with MUTYH-related disease (PMID: 19394335, 27829682; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.428C>T (p.Pro143Leu). ClinVar contains an entry for this variant (Variation ID: 185653). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 25820570). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165108	SCV000905865	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 157 of the MUTYH protein. This variant is also known as c.428C>T (p.Pro143Leu) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a partial loss of MUTYH protein function in vitro (PMID: 25820570). This variant has been reported in at least two biallelic individuals (PMID: 16557584, 19032956 19732775, 27829682) and a homozygous individual affected with multiple adenomatous polyposis and/or colorectal cancer (PMID: 19394335). This variant has been identified in 2/281716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000226581	SCV002017835	likely pathogenic	Familial adenomatous polyposis 2	2019-01-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000226581	SCV004199429	likely pathogenic	Familial adenomatous polyposis 2	2024-02-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000226581	SCV004847969	likely pathogenic	Familial adenomatous polyposis 2	2024-03-22	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV001355674	SCV005396366	likely pathogenic	not provided	2024-05-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate partially defective BER activity in a complementation assay, with normal protein expression and subcellular localization similar to wild type (PMID: 25820570); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.428G>A; This variant is associated with the following publications: (PMID: 19032956, 25525159, 19732775, 27829682, 19725997, 16557584, 19394335, 25820570)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355674	SCV001550625	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000226581	SCV004228644	not provided	Familial adenomatous polyposis 2		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-25-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.