Submissions for variant NM_000535.7(PMS2):c.1686T>A (p.Phe562Leu)

dbSNP: rs764749700

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482112	SCV000567503	uncertain significance	not provided	2018-03-22	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1686T>A at the cDNA level, p.Phe562Leu (F562L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Phe562Leu was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Phe562Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000554303	SCV000625549	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	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 562 of the PMS2 protein (p.Phe562Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 419597). 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 not expected to disrupt PMS2 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV000771397	SCV000903740	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 562 of the PMS2 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 not been reported in individuals affected with PMS2-related disorders in the literature. 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.
Ambry Genetics	RCV000771397	SCV001173195	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-11	criteria provided, single submitter	clinical testing	The c.1686T>A (p.F562L) alteration is located in exon 11 (coding exon 11) of the PMS2 gene. This alteration results from a T to A substitution at nucleotide position 1686, causing the phenylalanine (F) at amino acid position 562 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222525	SCV002500788	uncertain significance	not specified	2022-03-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481507	SCV002792127	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002306	SCV004844158	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 562 of the PMS2 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 not been reported in individuals affected with PMS2-related disorders in the literature. 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.