Submissions for variant NM_001048174.2(MUTYH):c.299A>G (p.Tyr100Cys)

dbSNP: rs876660615

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218591	SCV000278188	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-10-07	criteria provided, single submitter	clinical testing	The p.Y128C variant (also known as c.383A>G), located in coding exon 4 of the MUTYH gene, results from an A to G substitution at nucleotide position 383. The tyrosine at codon 128 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified likely in trans with two different MUTYH pathogenic variants in individuals diagnosed with MUTYH-associated polyposis (Ambry internal data). Based on internal structural analysis, Y128C is deleterious; the variant is moderately destabilizing to the local structure (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559697	SCV000639317	likely pathogenic	Familial adenomatous polyposis 2	2024-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 128 of the MUTYH protein (p.Tyr128Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis (external communication, internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 233751). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000218591	SCV000904797	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 128 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 not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified 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	RCV000218591	SCV002532280	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000559697	SCV004837809	uncertain significance	Familial adenomatous polyposis 2	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 128 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 not been identified 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	RCV000559697	SCV005056080	uncertain significance	Familial adenomatous polyposis 2	2023-12-15	criteria provided, single submitter	clinical testing