Submissions for variant NM_001048174.2(MUTYH):c.32G>A (p.Gly11Asp)

gnomAD frequency: 0.00044  dbSNP: rs75321043

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123155	SCV000166459	benign	Familial adenomatous polyposis 2	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129347	SCV000184111	benign	Hereditary cancer-predisposing syndrome	2017-04-03	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000034680	SCV000211396	likely benign	not provided	2021-06-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18422726, 22641385, 22703879, 11295288, 17252231, 30333958, 29879026, 18811933, 16929514, 25820570, 26684191, 26900293, 25980754, 27443514, 26332594, 24728327, 17703316, 27600092, 29330641, 29667044)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000123155	SCV000267405	uncertain significance	Familial adenomatous polyposis 2	2016-03-18	criteria provided, single submitter	reference population
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121606	SCV000539815	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.3% (114/8654) East Asian chromosomes; ClinVar: 4 labs classify as VUS
Color Diagnostics, LLC DBA Color Health	RCV000129347	SCV000690606	benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034680	SCV000697710	benign	not provided	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.74G>A (p.Gly25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.001112 (135/121410 chrs tested), predominantly observed in the East Asian subpopulation (0.013; 114/8654 chrs, including 2 homozygotes). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. Most of the published reports indicate that c.74G>A co-occurs in cis with c.53C>T (P18L). Although c.[53C>T; 74G>A] haplotype has been reported to be enriched in sporadic CRC pts compared to controls (Chen, 2008), in functional studies both the complex allele and its compounds were shown to retain complementation ability and were considered to be functionally neutral. In addition, several reported CRC pts carried known pathogenic variants (APC c.3595_3596delAA (p.Lys1199Glufs), MSH6 c.3724_3726del (p.Arg1242del) , that could have explain CRC phenotype in these families (Taki, 2016, Ring, 2012). Lastly, several reputable databases/diagnostic centers classified the variant of interest as VUS/ Benign. Taking together, by applying ACMG rules, the variant was classified as Benign.
Counsyl	RCV000123155	SCV000788437	uncertain significance	Familial adenomatous polyposis 2	2017-11-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121606	SCV000806367	benign	not specified	2017-08-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000123155	SCV001135267	benign	Familial adenomatous polyposis 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034680	SCV001147275	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MUTYH: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034680	SCV001159515	benign	not provided	2023-04-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000123155	SCV001257715	uncertain significance	Familial adenomatous polyposis 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034680	SCV001469577	likely benign	not provided	2023-06-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129347	SCV002532328	benign	Hereditary cancer-predisposing syndrome	2020-08-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121606	SCV002552531	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034680	SCV000043379	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121606	SCV000085804	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353637	SCV000592675	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Gly25Asp variant was identified in the literature in 18 of 896 proband chromosomes (frequency: 0.020) from Asian individuals (Korean, Chinese, Japanese) with adenomatous polyposis or colorectal cancer, and was present in 6 of 944 control chromosomes (frequency: 0.006) (Chen 2008, Kim 2007, Yanaru-Fujisawa 2008, Zhang 2006). In all these studies, the variant was identified in co-occurrence on the same allele as another MUTYH variant, p.Pro18Leu. Two studies suggest that this haplotype variant allele (containing both p.Pro18Leu and p.Gly25Asp variants) increases the risk of gastric cancer, with significantly higher frequencies of the variant haplotype observed in affected cases than in healthy controls (Chen 2008, Zhang 2006). In addition, a functional study by Chen (2008) found that the haplotype variant allele had a partial effect on protein mitochondrial transport as compared to wild type MUTYH protein. This effect, however, was not found when each variant was tested individually, suggesting an additive effect of the combined variants on the mitochondrial targeting sequences domain of the MUTYH protein. The variant was also identified in dbSNP (ID: rs75321043) “With allele of Uncertain significance” with a minor allele frequency of 0.003 (1000 Genomes Project), in HGMD, and in the “InSiGHT Colon Cancer Database”. The p.Gly25 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as a variant of unknown significance (VUS).