Submissions for variant NM_000535.7(PMS2):c.1268C>G (p.Ala423Gly)

gnomAD frequency: 0.00038  dbSNP: rs756883400

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164345	SCV000214978	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	The p.A423G variant (also known as c.1268C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1268. The alanine at codon 423 is replaced by glycine, an amino acid with similar properties. This alteration was reported to co-occur with a pathogenic MLH1 mutation in an individual with a Lynch syndrome associated cancer and/or colorectal polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This variant was reported in 12/60,466 breast cancer cases and in 9/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also identified in a cohort of pancreatic cancer patients undergoing multigene panel testing (Young EL et al. BMC Cancer, 2018 Jun;18:697). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524430	SCV000285058	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000234512	SCV000469735	uncertain significance	Lynch syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000657013	SCV000566388	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with pancreatic cancer and in an individual with a Lynch-associated cancer and/or polyps who also harbored a pathogenic MLH1 variant (Yurgelun et al., 2015; Young et al., 2018); Case control studies suggest this variant may be associated with breast cancer (Nikitin et al., 2020); This variant is associated with the following publications: (PMID: 27882345, 27363283, 25980754, 29945567, 32547938, 33471991)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657013	SCV000601812	uncertain significance	not provided	2022-12-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00014 (18/128902 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported to co-occur with an MLH1 variant in an individual with Lynch Syndrome (PMID: 25980754 (2015). Additionally, the variant has been reported in individuals with breast cancer (PMIDs: 32547938 (2020) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PMS2)) and healthy individuals (PMID: 33471991, see also LOVD (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.
Color Diagnostics, LLC DBA Color Health	RCV000164345	SCV000686116	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 423 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 performed for this variant. This variant has been reported in one individual tested for Lynch syndrome in the literature, however this individual also harbored a pathogenic MLH1 mutation (PMID: 25980754). This variant has also been reported in 12/60466 cases and 9/53461 unaffected controls in a large breast cancer case-control study (PMID: 33471991). This variant has been identified in 19/282400 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.
Genetic Services Laboratory, University of Chicago	RCV000486789	SCV002067550	uncertain significance	not specified	2018-10-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164345	SCV002529780	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000486789	SCV002550723	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000486789	SCV004020715	uncertain significance	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1268C>G (p.Ala423Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251004 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1268C>G has been reported in the literature in an individual suspected of Lynch Syndrome who also had a co-occurring pathogenic variant in MLH1 (c.1852_1854del, p.Lys618del), providing supporting evidence for a benign role (Yurgelun_2015). It has also been reported in settings of multigene panel testing in individuals affected with breast cancer and pancreatic cancer (Young_2018, Niktin_2020). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32547938, 29945567, 25980754). Nine 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.
CeGaT Center for Human Genetics Tuebingen	RCV000657013	SCV004042288	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	PMS2: PS4:Supporting, BP1, BP5
Baylor Genetics	RCV000234512	SCV004205457	uncertain significance	Lynch syndrome 4	2024-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005042328	SCV005674330	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2024-06-18	criteria provided, single submitter	clinical testing