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 The p.L236F variant (also known as c.708G>T), located in coding exon 7 of the PMS2 gene, results from a G to T substitution at nucleotide position 708. The leucine at codon 236 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is 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.
Invitae RCV000231924 SCV000285149 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-03 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290448 SCV000697378 uncertain significance not specified 2021-01-27 criteria provided, single submitter clinical testing Variant summary: PMS2 c.708G>T (p.Leu236Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of 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 4.3e-05 in 184566 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.708G>T in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The variant has been cited in at least one individual from a database of individuals affected with atherosclerosis phenotypes (e.g. Johnston_2012, Pinard_2016) and in a colorectal tumor (germline vs. somatic origin not determined, Pannuti_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These laboratories cited the variant as uncertain significance (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc 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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