Submissions for variant NM_000535.7(PMS2):c.983A>G (p.Asp328Gly)

gnomAD frequency: 0.00001  dbSNP: rs587782852

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132452	SCV000187546	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The p.D328G variant (also known as c.983A>G), located in coding exon 9 of the PMS2 gene, results from an A to G substitution at nucleotide position 983. The aspartic acid at codon 328 is replaced by glycine, an amino acid with similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod Pathol, 2016 Nov;29:1381-1389). 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.
GeneDx	RCV000656944	SCV000279136	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22949387, 27443514, 23017166, 11574484, 35264596, 29684080, 35449176, 34371384)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226690	SCV000285167	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 328 of the PMS2 protein (p.Asp328Gly). This variant is present in population databases (rs587782852, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 23017166, 27443514, 34371384, 35264596). ClinVar contains an entry for this variant (Variation ID: 142960). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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.
Counsyl	RCV000411483	SCV000488354	uncertain significance	Lynch syndrome 4	2016-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000214828	SCV000596478	uncertain significance	not specified	2017-04-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132452	SCV000686262	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 328 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 individuals affected with colorectal cancer (PMID: 23017166, 29684080) and endometrial cancer (PMID: 27443514). This variant has been identified in 6/251110 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.
Mendelics	RCV000708988	SCV000838184	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000214828	SCV000918049	uncertain significance	not specified	2023-03-06	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.983A>G (p.Asp328Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) 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 2.4e-05 in 251110 control chromosomes (gnomAD). This observation needs to be cautiously considered due to the inability of the technology used to detect between the PMS2 gene and its pseudogene. Thus, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.983A>G has been reported in the literature in settings of multigene panel testing in individuals affected with breast, ovarian and endometrial cancers, as well as in an individual with colorectal cancer whose tumors showed loss of MLH1 and PMS2 by IHC (e.g. Clendenning_2013, Ring_2016, Bono_2021, Guindalini_2022). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000411483	SCV004019818	likely benign	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
PreventionGenetics, part of Exact Sciences	RCV003390826	SCV004110285	uncertain significance	PMS2-related disorder	2023-03-28	criteria provided, single submitter	clinical testing	The PMS2 c.983A>G variant is predicted to result in the amino acid substitution p.Asp328Gly. This variant has been reported in individuals with PMS2 related phenotypes including colorectal and endometrial cancers; however no functional or family segregation studies have confirmed its pathogenicity (Clendenning et al. 2012. PubMed ID: 23017166; Ring et al. 2016. PubMed ID: 27443514; Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6031609-T-C). In ClinVar, this change is classified as a variant of uncertain significance by numerous clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/142960/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000411483	SCV004205410	uncertain significance	Lynch syndrome 4	2024-02-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656944	SCV004219040	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with endometrial cancer (PMID: 27443514 (2016), breast cancer (PMID: 35449176 (2022), 35264596 (2022), and ovarian cancer (PMID: 34371384 (2021)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). The frequency of this variant in the general population, 0.000044 (5/113648 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000708988	SCV004839869	uncertain significance	Lynch syndrome	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 328 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 individuals affected with colorectal cancer (PMID: 23017166, 29684080) and endometrial cancer (PMID: 27443514). This variant has been identified in 6/251110 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.