Submissions for variant NM_000535.7(PMS2):c.2380C>T (p.Pro794Ser)

dbSNP: rs773393960

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204089	SCV000261530	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568777	SCV000674232	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	The p.P794S variant (also known as c.2380C>T), located in coding exon 14 of the PMS2 gene, results from a C to T substitution at nucleotide position 2380. The proline at codon 794 is replaced by serine, an amino acid with similar properties. 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.
Counsyl	RCV000662637	SCV000785323	uncertain significance	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764721	SCV000895856	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328413	SCV001519528	uncertain significance	not specified	2022-06-21	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2380C>T (p.Pro794Ser) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247958 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 confirmed occurrence of c.2380C>T as originating in the PMS2 gene and not the PMS2CL pseudogene in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Although this variant has been reported in the literature in at-least two individuals with familial colorectal cancer who demonstrated MSHI-high tumor and normal IHC staining for MLH1, MSH2, MSH6 and PMS2 proteins, the sequencing methodology employed precludes unequivocal interpretation of this finding in the context of the PMS2 gene and is therefore not weighted in the context of this evaluation (example, Liccardo_2019). Five 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.
GeneDx	RCV001753620	SCV002005026	uncertain significance	not provided	2021-08-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome (Liccardo 2019); This variant is associated with the following publications: (PMID: 21552516, 31410062, 31258848)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150094	SCV003838380	uncertain significance	Breast and/or ovarian cancer	2022-05-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662637	SCV004019835	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001328413	SCV004243278	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568777	SCV004358999	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 794 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with colorectal cancer whose tumors showed normal expression of PMS2, MLH1, MSH2 and MSH6 (PMID: 31410062). This variant has been identified in 2/247772 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.