Submissions for variant NM_001048174.2(MUTYH):c.887C>T (p.Ser296Leu)

gnomAD frequency: 0.00001  dbSNP: rs558173961

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766300	SCV000211415	uncertain significance	not provided	2020-03-05	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 does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000213585	SCV000276117	likely benign	Hereditary cancer-predisposing syndrome	2018-09-24	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766300	SCV000601666	uncertain significance	not provided	2020-02-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552627	SCV000639368	uncertain significance	Familial adenomatous polyposis 2	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 324 of the MUTYH protein (p.Ser324Leu). This variant is present in population databases (rs558173961, gnomAD 0.01%). 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: 182695). 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 leucine 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.
Counsyl	RCV000552627	SCV000797228	uncertain significance	Familial adenomatous polyposis 2	2018-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213585	SCV000905859	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 324 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 been detected in a breast cancer case-control meta-analysis in 1/60466 cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251458 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.
Mendelics	RCV000552627	SCV001135256	likely benign	Familial adenomatous polyposis 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844058	SCV002103590	uncertain significance	not specified	2022-02-03	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.971C>T (p.Ser324Leu) 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. The variant allele was found at a frequency of 1.2e-05 in 251458 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.971C>T has been reported in the literature in individuals affected with Breast Cancer without strong evidence for causality (Maxwell_2015, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis or Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrence of the variant with another pathogenic variant has been reported in our laboratory (BRCA1 c.68_69delAG, p.E23fs*17), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000552627	SCV004198943	uncertain significance	Familial adenomatous polyposis 2	2023-05-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000552627	SCV004835270	uncertain significance	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 324 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 been detected in a breast cancer case-control meta-analysis in 1/60466 cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251458 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.