Submissions for variant NM_001048174.2(MUTYH):c.1472G>A (p.Arg491Gln)

gnomAD frequency: 0.00003  dbSNP: rs369410616

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115761	SCV000149670	uncertain significance	not provided	2021-03-25	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Nones 2019); This variant is associated with the following publications: (PMID: 31090900)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123146	SCV000166449	uncertain significance	Familial adenomatous polyposis 2	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 519 of the MUTYH protein (p.Arg519Gln). This variant is present in population databases (rs369410616, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 31090900). ClinVar contains an entry for this variant (Variation ID: 127841). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Ambry Genetics	RCV000216371	SCV000273075	likely benign	Hereditary cancer-predisposing syndrome	2017-11-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000216371	SCV000690536	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 519 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 31090900, 33471991). In a large international case-control study, this variant was reported in 4/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 6/282814 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.
Counsyl	RCV000123146	SCV000793684	uncertain significance	Familial adenomatous polyposis 2	2017-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731381	SCV001983535	likely benign	not specified	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1556G>A (p.Arg519Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1556G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Nones_2019). A risk association study showed that this variant is not associated with Hereditary Breast And Ovarian Cancer Syndrome (Dorling_2021, LOVD database, p=0.6). Co-occurrence with a pathogenic variant has been reported (BRCA1 c.5244_5245delAA, p.Lys1748fs, Nones_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=3, likely benign n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV000123146	SCV004198804	uncertain significance	Familial adenomatous polyposis 2	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123146	SCV004830343	uncertain significance	Familial adenomatous polyposis 2	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 519 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 31090900, 33471991). In a large international case-control study, this variant was reported in 4/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 6/282814 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001731381	SCV005090476	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing