ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1031C>T (p.Ser344Phe)

dbSNP: rs763862261
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474861 SCV000545759 uncertain significance Familial adenomatous polyposis 2 2023-10-09 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 372 of the MUTYH protein (p.Ser372Phe). This variant is present in population databases (rs763862261, gnomAD 0.006%). 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: 406844). 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.
Ambry Genetics RCV000562681 SCV000666460 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing The p.S372F variant (also known as c.1115C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1115. The serine at codon 372 is replaced by phenylalanine, an amino acid with highly dissimilar 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.
Color Diagnostics, LLC DBA Color Health RCV000562681 SCV000685540 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-12 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 372 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 reported in individuals affected with breast cancer (PMID: 29684080, 33471991). This variant has been identified in 1/250516 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000605918 SCV000731550 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing The p.Ser372Phe variant in MUTYH has not been previously reported in the literat ure, but has been reported in ClinVar (Variation ID 406844). It has also been id entified in 1/17244 of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763862261). Although this va riant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Serine (Ser) at position 372 is not conserved in mammals or evolutionarily distant species, raising the possibility that a change at this position may be tolerated. Additionally, computational prediction tools do not provide strong support for or against an impact to the protein. In summa ry, the clinical significance of the p.Ser372Phe variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000605918 SCV001774638 uncertain significance not specified 2021-07-19 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1115C>T (p.Ser372Phe) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250516 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.1115C>T in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four 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.
Fulgent Genetics, Fulgent Genetics RCV002506112 SCV002815460 uncertain significance Familial adenomatous polyposis 2; Gastric cancer 2022-05-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000474861 SCV004198880 uncertain significance Familial adenomatous polyposis 2 2023-08-29 criteria provided, single submitter clinical testing

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