Submissions for variant NM_001048174.2(MUTYH):c.614G>A (p.Gly205Asp)

gnomAD frequency: 0.00001  dbSNP: rs147487160

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460021	SCV000545746	uncertain significance	Familial adenomatous polyposis 2	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 233 of the MUTYH protein (p.Gly233Asp). This variant is present in population databases (rs147487160, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560; Invitae). This missense change has been observed to co-occur in individuals with a different variant in MUTYH that has been determined to be pathogenic (PMID: 27978560; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 406839). 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 disruptive. 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	RCV000480983	SCV000571095	uncertain significance	not provided	2019-08-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Co-occurred with MUTYH p.Gly396Asp in an individual with MMR-deficient colorectal cancer and multiple adenomas (Pearlman 2017); This variant is associated with the following publications: (PMID: 27978560)
Ambry Genetics	RCV000567412	SCV000670162	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-28	criteria provided, single submitter	clinical testing	The p.G233D variant (also known as c.698G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 698. The glycine at codon 233 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a patient with multiple polyps and colorectal cancer diagnosed at age 39; this individual was also found to carry the MUTYH p.G396D founder mutation (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). Based on internal structural analysis, G233D is strongly disruptive to the active site of MUTYH, a region enriched with pathogenic variants (Guan Y et al. Nat Struct Biol, 1998 Dec;5:1058-64; Luncsford PJ et al. J Mol Biol, 2010 Oct;403:351-70; Manuel RC et al. J Biol Chem, 2004 Nov;279:46930-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000567412	SCV000907357	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a pathogenic co-variant in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 2/250678 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.
Fulgent Genetics, Fulgent Genetics	RCV002480377	SCV002785410	uncertain significance	Familial adenomatous polyposis 2; Gastric cancer	2022-03-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000460021	SCV004841448	uncertain significance	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 233 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a pathogenic co-variant in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 2/250678 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	RCV000460021	SCV005056037	uncertain significance	Familial adenomatous polyposis 2	2024-03-09	criteria provided, single submitter	clinical testing