Submissions for variant NM_001048174.2(MUTYH):c.848G>A (p.Arg283Lys)

gnomAD frequency: 0.00021  dbSNP: rs149342980

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590230	SCV000211412	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Observed in individuals with ovarian, lung, breast, or colon cancer (Lu 2015, Tung 2015, Pearlman 2017); Observed with a pathogenic MUTYH variant, phase (cis or trans) unknown, in a patient with suspected MUTYH-associated polyposis, however other variants of uncertain significance in MUTYH and other genes were also identified in this patient (Dell'Elice 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as Arg297Lys; This variant is associated with the following publications: (PMID: 26689913, 27978560, 25186627, 11092888, 11160897, 16879101, 20816984, 34704405)
Ambry Genetics	RCV000160757	SCV000215183	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	The p.R311K variant (also known as c.932G>A), located in coding exon 10 of the MUTYH gene, results from a G to A substitution at nucleotide position 932. The arginine at codon 311 is replaced by lysine, an amino acid with highly similar properties. This alteration was reported in the germline of an individual with ovarian cancer from a cohort of 4034 individuals with cancer undergoing whole exome sequencing (Lu C et al. Nat. Commun. 2015 Dec;6:10086). This variant was observed in an individual diagnosed with breast cancer greater than age 50 and was considered low-risk based on family history (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration has also been identified in a female proband diagnosed at age 37 with colon cancer and in a female proband diagnosed with colorectal cancer in her 60s, but no co-occurring pathogenic variants in MUTYH were reported for either patient (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Georgeson P et al. Nat Commun, 2022 06;13:3254). This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000168393	SCV000219086	uncertain significance	Familial adenomatous polyposis 2	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 311 of the MUTYH protein (p.Arg311Lys). This variant is present in population databases (rs149342980, gnomAD 0.08%). This missense change has been observed in individual(s) with ovarian, breast, colon cancer and colorectal polyposis (PMID: 25186627, 26689913, 27978560, 35264596). This variant is also known as c.890G>A (p.Arg297Lys). ClinVar contains an entry for this variant (Variation ID: 182694). 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 lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Illumina Laboratory Services, Illumina	RCV000168393	SCV000357897	uncertain significance	Familial adenomatous polyposis 2	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000168393	SCV000487364	uncertain significance	Familial adenomatous polyposis 2	2016-06-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590230	SCV000601663	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with colorectal cancer (PMIDs: 35668106 (2022), 27978560 (2016)), breast cancer (PMID: 25186627 (2015)), and ovarian cancer or lung cancer (PMID: 26689913 (2015)). The frequency of this variant in the general population, 0.0008 (20/24940 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212710	SCV000697715	uncertain significance	not specified	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.932G>A (p.Arg311Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251388 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00011 vs 0.0046), allowing no conclusion about variant significance. c.932G>A has been reported in the literature in individuals affected with different types of cancers including Colorectal Cancer, Pancreatic Cancer, Breast Cancer and other unspecified cancer (example, Tung_2015, Lu_2015, Pearlman_2016, Zhu_2021, Guindalini_2022, Bhai_2021). It has also been reported in both case and control cohorts of a large case-control study of Breast Cancer (Dorling_2021. 3/60466 cases vs 5/53461 controls). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 35264596, 26689913, 27978560, 25186627, 33939675, 33471991). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000590230	SCV000806371	uncertain significance	not provided	2017-02-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000168393	SCV000837760	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765175	SCV000896408	uncertain significance	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160757	SCV000910764	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 311 of the MUTYH protein. This variant is also known as NM_001048171.1:c.890G>A (p.Arg297Lys) in the literature. 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 observed in individuals affected with colon, ovarian, breast and lung cancer (PMID: 25186627, 26689913, 27978560, 33471991, 35668106) as well as in an individual potentially biallelic and affected with MUTYH-associated polyposis (PMID: 34704405). This variant has been identified in 36/282768 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.
Sema4, Sema4	RCV000160757	SCV002532344	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-21	criteria provided, single submitter	curation
Baylor Genetics	RCV000168393	SCV004198850	uncertain significance	Familial adenomatous polyposis 2	2023-09-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000168393	SCV004236653	uncertain significance	Familial adenomatous polyposis 2	2023-06-14	criteria provided, single submitter	clinical testing