Submissions for variant NM_001048174.2(MUTYH):c.295G>A (p.Ala99Thr)

dbSNP: rs746112825

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214239	SCV000274013	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-12	criteria provided, single submitter	clinical testing	The p.A127T variant (also known as c.379G>A), located in coding exon 4 of the MUTYH gene, results from a G to A substitution at nucleotide position 379. The alanine at codon 127 is replaced by threonine, an amino acid with similar properties. This variant has been detected in conjunction with a MUTYH pathogenic variant in at least two individuals with clinical features of MUTYH-associated disease; however, the phase of the two variants is unknown (Ambry internal data; personal communication). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000482082	SCV000566086	uncertain significance	not provided	2019-08-20	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699073	SCV000827768	uncertain significance	Familial adenomatous polyposis 2	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 127 of the MUTYH protein (p.Ala127Thr). This variant is present in population databases (rs746112825, gnomAD 0.0009%). 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: 230457). 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.
Color Diagnostics, LLC DBA Color Health	RCV000214239	SCV004358600	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 127 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 MUTYH-related disorders in the literature. This variant has been identified in 1/251332 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.
All of Us Research Program, National Institutes of Health	RCV000699073	SCV004833486	uncertain significance	Familial adenomatous polyposis 2	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 127 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 MUTYH-related disorders in the literature. This variant has been identified in 1/251332 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	RCV000699073	SCV005056039	uncertain significance	Familial adenomatous polyposis 2	2024-03-08	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596116	SCV005090653	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing