ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.708G>T (p.Leu236Phe) (rs201395630)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165656 SCV000216393 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-13 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000231924 SCV000285149 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 236 of the PMS2 protein (p.Leu236Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs201395630, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 41718). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.
Counsyl RCV000412437 SCV000489520 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-10-18 criteria provided, single submitter clinical testing
GeneDx RCV000034634 SCV000565388 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.708G>T at the cDNA level, p.Leu236Phe (L236F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTT). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). PMS2 Leu236Phe was not observed in large population cohorts (Lek 2016). This variant is located in ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Leu236Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000034634 SCV000697378 uncertain significance not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.708G>T variant affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was found in 3/83126 control chromosomes at a frequency of 0.000036, which does not exceed maximal expected frequency of a pathogenic PMS2 allele (0.0001136); and it cannot be ruled out that these occurrences were observed due to pseudogene interference. In addition, two clinical laboratories classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV000165656 SCV000911382 likely benign Hereditary cancer-predisposing syndrome 2016-01-15 criteria provided, single submitter clinical testing
Mendelics RCV000412437 SCV001137317 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034634 SCV000043434 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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