ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.995C>T (p.Ser332Leu) (rs587778538)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123137 SCV000166439 uncertain significance MYH-associated polyposis 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 346 of the MUTYH protein (p.Ser346Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs587778538, ExAC 0.03%). This variant has been reported in an individual undergoing Lynch syndrome genetic testing (PMID: 25980754) and in individuals affected with breast and/or ovarian cancer (PMID: 25186627, 30982232). ClinVar contains an entry for this variant (Variation ID: 134862). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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 RCV000216934 SCV000275946 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing The p.S346L variant (also known as c.1037C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1037. The serine at codon 346 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This amino acid position is poorly 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 RCV000123137 SCV000487349 uncertain significance MYH-associated polyposis 2016-04-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000216934 SCV001346480 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-21 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 346 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 an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in two individual affected with breast and/or ovarian cancer (PMID: 25186627). This variant has been identified in 14/273222 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 RCV000121595 SCV001370687 uncertain significance not specified 2020-05-26 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1037C>T (p.Ser346Leu) results in a non-conservative amino acid change in 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 5.4e-05 in 241834 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (5.4e-05 vs 0.0046), allowing no conclusion about variant significance. c.1037C>T has been reported in the literature in sequencing studies of individuals affected with and/or undergoing testing for breast cancer, colorectal cancer (example, Tung_2015, Yurgelun_2015, Wang_2019). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.
ITMI RCV000121595 SCV000085791 not provided not specified 2013-09-19 no assertion provided reference population

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