Submissions for variant NM_000535.7(PMS2):c.1432A>G (p.Ser478Gly)

gnomAD frequency: 0.00005  dbSNP: rs144389038

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166020	SCV000216779	likely benign	Hereditary cancer-predisposing syndrome	2018-09-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000200794	SCV000254597	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 478 of the PMS2 protein (p.Ser478Gly). This variant is present in population databases (rs144389038, 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: 186428). 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	RCV001721076	SCV000518450	likely benign	not provided	2021-09-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166020	SCV000909654	likely benign	Hereditary cancer-predisposing syndrome	2017-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423126	SCV000920049	uncertain significance	not specified	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1432A>G (p.Ser478Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 121410 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 occurrence of c.1432A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 likely benign, 2 VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000987830	SCV001137299	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001721076	SCV004218954	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251490 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer co-occurring with a MSH2 variant of uncertain significance (PMID: 32885271 (2021)). In a large breast cancer association study, the variant was found in one unaffected individual (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354397	SCV001549005	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Ser478Gly variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database or Insight Hereditary Tumors Database, databases. The variant was identified in dbSNP (ID: rs144389038) as “With Uncertain significance allele” and ClinVar (3x as likely benign by GeneDx, as uncertain significance by Ambry Genetics and Invitae) databases. The variant was identified in control databases in 2 of 246266 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15304 chromosomes (freq: 0.000065), Latino in 1 of 33582 chromosomes (freq: 0.00003), while the variant was not observed in the Other, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser478 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.