Submissions for variant NM_001128425.2(MUTYH):c.38C>T (p.Ala13Val)

gnomAD frequency: 0.00001  dbSNP: rs587780747

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123150	SCV000166453	uncertain significance	Familial adenomatous polyposis 2	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 13 of the MUTYH protein (p.Ala13Val). This variant is present in population databases (rs587780747, gnomAD 0.003%). This missense change has been observed in individual(s) with MUTYH-related conditions (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 135987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000131635	SCV000186659	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	The p.A13V variant (also known as c.38C>T), located in coding exon 2 of the MUTYH gene, results from a C to T substitution at nucleotide position 38. The alanine at codon 13 is replaced by valine, 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.
Counsyl	RCV000123150	SCV000487325	uncertain significance	Familial adenomatous polyposis 2	2015-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000485844	SCV000569382	uncertain significance	not provided	2024-05-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in an individual with breast cancer (PMID: 34326862); This variant is associated with the following publications: (PMID: 23108399, 35628513, 34326862, 38074417)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131635	SCV000679734	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131635	SCV000685625	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 13 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 hereditary cancer in the literature. This variant has been identified in 3/251466 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	RCV001260346	SCV001437279	uncertain significance	not specified	2020-09-04	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.38C>T (p.Ala13Val) 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251466 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.38C>T in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485844	SCV004222086	uncertain significance	not provided	2022-09-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000026 (3/113748 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale case-control study, this variant has been reported in individuals with breast cancer and none of the unaffected controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ MUTYH)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000123150	SCV004835782	uncertain significance	Familial adenomatous polyposis 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 13 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 hereditary cancer in the literature. This variant has been identified in 3/251466 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.