ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.487T>C (p.Phe163Leu)

dbSNP: rs587780060
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000985911 SCV000149606 uncertain significance not provided 2023-07-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with colorectal or breast cancer (Yurgelun et al., 2017; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 22949387, 28135145, 28873162, 32118206, 33471991, 11574484)
Ambry Genetics RCV000115697 SCV000212838 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-09 criteria provided, single submitter clinical testing The p.F163L variant (also known as c.487T>C), located in coding exon 5 of the PMS2 gene, results from a T to C substitution at nucleotide position 487. The phenylalanine at codon 163 is replaced by leucine, an amino acid with highly similar properties. This alteration, classified as a variant of unknown significance, was detected in a cohort of 1058 patients with colorectal cancer (Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095) and in a cohort of 1040 individuals with advanced cancer undergoing paried tumor-normal DNA testing (Mandelker D et al. JAMA, 2017 Sep;318:825-835). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000227288 SCV000285136 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 163 of the PMS2 protein (p.Phe163Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal and breast cancer (PMID: 28135145, 34326862). ClinVar contains an entry for this variant (Variation ID: 127792). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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 RCV000411957 SCV000489637 uncertain significance Lynch syndrome 4 2016-11-08 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000515175 SCV000611424 uncertain significance Mismatch repair cancer syndrome 1; Lynch syndrome 4 2017-05-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115697 SCV000686209 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-08 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with leucine at codon 163 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145) and unspecified cancer (PMID: 28873162). In a large breast cancer case-control study, this variant has been reported in 4/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985911 SCV001134604 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115697 SCV002530349 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-06 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000411957 SCV004019809 uncertain significance Lynch syndrome 4 2023-04-04 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

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