Submissions for variant NM_001128425.2(MUTYH):c.17C>A (p.Ser6Tyr)

gnomAD frequency: 0.00002  dbSNP: rs587782837

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132425	SCV000187518	likely benign	Hereditary cancer-predisposing syndrome	2024-04-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000656906	SCV000211397	uncertain significance	not provided	2023-10-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast or other cancers (PMID: 27720647, 25186627); This variant is associated with the following publications: (PMID: 23108399, 25186627, 27720647)
Invitae	RCV000458224	SCV000545760	uncertain significance	Familial adenomatous polyposis 2	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 6 of the MUTYH protein (p.Ser6Tyr). This variant is present in population databases (rs587782837, gnomAD 0.08%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 142941). 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 tolerated. 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	RCV000132425	SCV000685602	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine at codon 6 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 27/280764 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.
PreventionGenetics, part of Exact Sciences	RCV000656906	SCV000806352	uncertain significance	not provided	2017-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212695	SCV000919798	uncertain significance	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.17C>A (p.Ser6Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 249362 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing Hereditary Breast And Ovarian Cancer Syndrome (9.6e-05 vs 0.0056), allowing no conclusion about variant significance. c.17C>A has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Tung_2014) or unspecified individual(s) undertaking cancel panel testing (Mu_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome or other MUTYH-related diseases. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27720647, 25186627). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters 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	RCV000656906	SCV001470569	uncertain significance	not provided	2023-02-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00076 (27/35360 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)). 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.
Baylor Genetics	RCV000458224	SCV001481434	uncertain significance	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483273	SCV002789632	uncertain significance	Familial adenomatous polyposis 2; Gastric cancer	2021-11-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000458224	SCV004835837	uncertain significance	Familial adenomatous polyposis 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine at codon 6 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 27/280764 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000212695	SCV000691954	uncertain significance	not specified		no assertion criteria provided	clinical testing