Submissions for variant NM_001048174.2(MUTYH):c.656G>A (p.Arg219Gln)

gnomAD frequency: 0.00001  dbSNP: rs777335285

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467495	SCV000545724	uncertain significance	Familial adenomatous polyposis 2	2023-06-14	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 247 of the MUTYH protein (p.Arg247Gln). This variant is present in population databases (rs777335285, gnomAD 0.006%). 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. This variant disrupts the p.Arg247 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been observed in individuals with MUTYH-related conditions (PMID: 31285513), which suggests that this may be a clinically significant amino acid residue. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 406828). This missense change has been observed in individual(s) with colonic polyps (PMID: 24470512; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV000582142	SCV000690605	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 247 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported biallelic and heterozygouls in individuals affected with MUTYH-associated polyposis, but phase and/or second mutation was not determined (PMID: 24470512, 29330641). This variant has been identified in 2/250424 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985863	SCV001134485	uncertain significance	not provided	2019-04-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582142	SCV001188774	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	The p.R247Q variant (also known as c.740G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 740. The arginine at codon 247 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified once in a cohort of 405 patients with at least 10 colonic polyps (Guarinos C et al. Clin. Cancer Res., 2014 Mar;20:1158-68), and in a cohort of 31 Japanese patients with suspected hereditary polyposis (Takao M et al. Int J Clin Oncol, 2018 Jun;23:497-503). This alteration was also detected in a cohort of 118 individuals with features suggestive of inherited renal cell carcinoma (Smith PS et al. Genes Chromosomes Cancer, 2021 Jan;60:5-16). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000467495	SCV004199407	uncertain significance	Familial adenomatous polyposis 2	2023-01-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000467495	SCV004839162	uncertain significance	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 247 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported biallelic and heterozygouls in individuals affected with MUTYH-associated polyposis, but phase and/or second mutation was not determined (PMID: 24470512, 29330641). This variant has been identified in 2/250424 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.