Submissions for variant NM_000535.7(PMS2):c.433C>A (p.Gln145Lys)

gnomAD frequency: 0.00002  dbSNP: rs786204133

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168105	SCV000218761	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 145 of the PMS2 protein (p.Gln145Lys). This variant is present in population databases (rs786204133, gnomAD 0.007%). 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: 188191). 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.
Ambry Genetics	RCV000222089	SCV000275555	likely benign	Hereditary cancer-predisposing syndrome	2020-02-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000585952	SCV000565382	uncertain significance	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with unspecified cancer who underwent multigene panel testing for Lynch syndrome (Li 2019); This variant is associated with the following publications: (PMID: 11574484, 31391288)
Color Diagnostics, LLC DBA Color Health	RCV000222089	SCV000691075	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 145 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 been detected in an individual affected with an unspecified Lynch syndrome-associated cancer (PMID: 31391288). In a large breast cancer case-control study, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585952	SCV000697369	uncertain significance	not provided	2017-03-20	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.433C>A (p.Gln145Lys) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121284 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Sema4, Sema4	RCV000222089	SCV002530344	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995608	SCV004839974	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 145 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 been detected in an individual affected with an unspecified Lynch syndrome-associated cancer (PMID: 31391288). In a large breast cancer case-control study, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991). 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.