Submissions for variant NM_001128425.2(MUTYH):c.167G>A (p.Gly56Glu)

gnomAD frequency: 0.00001  dbSNP: rs587781374

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165078	SCV000215780	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-27	criteria provided, single submitter	clinical testing	The p.G56E variant (also known as c.167G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 167. The glycine at codon 56 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is not well conserved in available 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197171	SCV000254707	uncertain significance	Familial adenomatous polyposis 2	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 56 of the MUTYH protein (p.Gly56Glu). This variant is present in population databases (rs587781374, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 185629). 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. 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.
GeneDx	RCV000236854	SCV000292811	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast cancer and in unaffected control(s) (PMID: 33471991); This variant is associated with the following publications: (PMID: 26689913, 33471991)
Counsyl	RCV000197171	SCV000791066	uncertain significance	Familial adenomatous polyposis 2	2017-04-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165078	SCV000905867	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 56 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 not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 8/274494 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264535	SCV001442739	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.167G>A (p.Gly56Glu) results in a non-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 2.8e-05 in 248342 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.167G>A in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Six 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.
Sema4, Sema4	RCV000165078	SCV002532264	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000197171	SCV004840346	uncertain significance	Familial adenomatous polyposis 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 56 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/274494 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.
Baylor Genetics	RCV000197171	SCV005056044	uncertain significance	Familial adenomatous polyposis 2	2024-02-21	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000236854	SCV001552797	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MUTYH p.G53E variant was not identified in the literature nor was it identified in LOVD 3.0, Cosmic or UMD-LSDB. The variant was identified in dbSNP (ID: rs587781374) and ClinVar (classified as uncertain significance by Counsyl, Ambry Genetics, GeneDx, Invitae and Color). The variant was identified in control databases in 8 of 279744 chromosomes at a frequency of 0.0000286 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7162 chromosomes (freq: 0.00014) and European (non-Finnish) in 7 of 127674 chromosomes (freq: 0.000055), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Gly53 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The p.Gly53 variant occurs in the first base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.