Submissions for variant NM_000535.7(PMS2):c.251C>G (p.Thr84Ser)

gnomAD frequency: 0.00003  dbSNP: rs864622274

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204858	SCV000259946	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 84 of the PMS2 protein (p.Thr84Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 219847). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000216278	SCV000273447	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-16	criteria provided, single submitter	clinical testing	The p.T84S variant (also known as c.251C>G) is located in coding exon 4 of the PMS2 gene. The threonine at codon 84 is replaced by serine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 4. RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with ALL (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is not well 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.
Counsyl	RCV000410342	SCV000489298	uncertain significance	Lynch syndrome 4	2016-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001705171	SCV000565381	uncertain significance	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with pediatric-onset acute lymphocytic leukemia (Zhang 2015); This variant is associated with the following publications: (PMID: 26580448, 11574484, 27535533)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000478536	SCV000918040	uncertain significance	not specified	2018-02-16	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.251C>G (p.Thr84Ser) results in a conservative amino acid change located in the Histidine kinase/HSP90-like ATPase of the encoded protein sequence, and is the first nucleotide of exon 4. Three of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 115026 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.251C>G has been reported in the literature in one individual affected with ALL (Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
Color Diagnostics, LLC DBA Color Health	RCV000216278	SCV001343153	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 84 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 been identified in 1/31404 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.
Myriad Genetics, Inc.	RCV000410342	SCV004019799	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.
Baylor Genetics	RCV000410342	SCV004205351	uncertain significance	Lynch syndrome 4	2023-10-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997585	SCV004842135	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 84 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 been identified in 1/31404 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.