Submissions for variant NM_001048174.2(MUTYH):c.484G>T (p.Ala162Ser)

dbSNP: rs764458059

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219640	SCV000277687	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-06	criteria provided, single submitter	clinical testing	The p.A190S variant (also known as c.568G>T), located in coding exon 7 of the MUTYH gene, results from a G to T substitution at nucleotide position 568. The alanine at codon 190 is replaced by serine, an amino acid with similar properties. 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 available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470639	SCV000545733	uncertain significance	Familial adenomatous polyposis 2	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 190 of the MUTYH protein (p.Ala190Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 233334). 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.
Mendelics	RCV000470639	SCV000837773	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219640	SCV001358554	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 190 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192932	SCV001361394	uncertain significance	not specified	2019-10-21	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.568G>T (p.Ala190Ser) results in a conservative amino acid change located in the HhH-GPD domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 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.568G>T in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000470639	SCV005056075	uncertain significance	Familial adenomatous polyposis 2	2023-12-28	criteria provided, single submitter	clinical testing
GeneDx	RCV004797799	SCV005419598	uncertain significance	not provided	2024-05-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or colorectal cancer (PMID: 35264596, 35534704); This variant is associated with the following publications: (PMID: 35264596, 35534704)