Submissions for variant NM_000535.7(PMS2):c.1379G>A (p.Gly460Asp)

gnomAD frequency: 0.00006  dbSNP: rs150201462

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131270	SCV000186238	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	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.
Invitae	RCV000477201	SCV000551969	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 460 of the PMS2 protein (p.Gly460Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with glioblastoma multiforme (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 142257). 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.
GeneDx	RCV000767041	SCV000565823	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with glioblastoma and in individuals with personal or family history of breast or ovarian cancer (Lu et al., 2015; Shao et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 27379089, 20186688, 26689913, 33471991, 31742824)
Counsyl	RCV000662638	SCV000785324	uncertain significance	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131270	SCV000911028	likely benign	Hereditary cancer-predisposing syndrome	2016-09-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000483100	SCV000920023	uncertain significance	not specified	2017-10-27	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.1379G>A (p.Gly460Asp) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index; SIFT tool not functioning). This variant was found in 3/30966 control chromosomes at a frequency of 0.0000969, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). However, this site did not pass quality control filters in the gnomAD database and the presence of a high homology PMS2 pseudogene also complicates the interpretation of this control data. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000483100	SCV000967508	uncertain significance	not specified	2018-10-16	criteria provided, single submitter	clinical testing	The p.Gly460Asp variant in PMS2 has not been reported in individuals with PMS2-a ssociated cancers, but has been reported by other clinical laboratories in ClinV ar (Variation ID: 142257). It has also been identified in 3/8728 African chromos omes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tool s and conservation analysis suggest that the p.Gly460Asp variant may not impact the protein. In summary, the clinical significance of the p.Gly460Asp variant is uncertain. ACMG/AMP Criteria applied: BP4.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767041	SCV001469606	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with glioblastoma multiforme (PMID: 26689913 (2015)). In a large breast cancer association study, the variant was reported in individuals with breast cancer and in healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PMS2)). The frequency of this variant in the general population, 0.00024 (6/24966 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000131270	SCV002529788	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662638	SCV004019810	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	RCV000483100	SCV004025117	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492618	SCV004239581	uncertain significance	Breast and/or ovarian cancer	2023-06-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998095	SCV004844229	likely benign	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353427	SCV000592933	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	PMS2, EXON11, c.1379G>A, p.Gly460Asp, Predicted Benign (ACMG 4) The PMS2 c.1379G>A variant was not identified in the literature nor was it identified in the COGR, HMGD, Mut, MMR, INSiGHT Colon Cancer or Zheilang Coln Cancer databases. It is listed in the dbSNP database (id#: rs150201462) and the variant was identified by the Exome Variant Server project in 1 of 13005 European American/African American alleles (frequency: 0.00007), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Gly460 residue is not conserved in mammals and the variant amino acid Leu is present in mouse and chicken, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The p.Gly460Asp variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.