Submissions for variant NM_000535.7(PMS2):c.1559C>T (p.Ala520Val)

gnomAD frequency: 0.00011  dbSNP: rs63751300

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164554	SCV000215212	likely benign	Hereditary cancer-predisposing syndrome	2018-09-11	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	RCV000200307	SCV000254600	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000411039	SCV000488683	uncertain significance	Lynch syndrome 4	2016-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000486349	SCV000565412	uncertain significance	not provided	2019-10-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with suspected Lynch syndrome (Yurgelun 2015, Lagerstedt-Robinson 2016, Okkels 2019); This variant is associated with the following publications: (PMID: 31433215, 27601186, 26232782, 20186688, 24362816, 17016615, 25980754, 22290698)
Fulgent Genetics, Fulgent Genetics	RCV000515358	SCV000611420	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164554	SCV000903023	likely benign	Hereditary cancer-predisposing syndrome	2016-04-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781744	SCV000920033	likely benign	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1559C>T (p.Ala520Val) 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 4.7e-05 in 1613986 control chromosomes, predominantly at a frequency of 0.00042 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD v4.0.0 database is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1559C>T has been reported in the literature in individuals affected with Lynch syndrome-associated cancers or with suspected Lynch Syndrome (e.g., Yurgelun_2015, Nomura_2015, Lagerstedt-Robinson_2016, Balogh_2006, Okkels_2019, Li_2020), frequently along with PMS2 c.1556A>G (p.Y519C; Yurgelun_2015, Nomura_2015, Okkels_2019). However, the variant was found not to segregate with disease in at least one family (e.g., Okkels_2019) and was also classified as a benign/likely benign polymorphism in several publications (e.g., Okkels_2019, Li_2020, Balogh_2006). These reports are not suggestive that the variant is associated with Lynch Syndrome. Additionally, co-occurrences with other pathogenic variants have been reported (MSH2 c.2210+1G>A (Yurgelun_2015); PMS2 c.1492_1502del11 (p.Ser498GlyfsX3; Nomura_2015); MLH1 c.677+3A>G (Okkels_2019); MLH1 c.(1731+1_1732-1)_(*194_?)del, E16-19del (Okkels_2019)), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting the variant does not disrupt protein function, however no data was shown (e.g., Okkels_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 17016615, 27601186, 31391288, 26232782, 31433215, 25980754). ClinVar contains an entry for this variant (Variation ID: 185185). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000486349	SCV001472552	likely benign	not provided	2019-12-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000486349	SCV002009111	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798585	SCV002042786	likely benign	Breast and/or ovarian cancer	2021-05-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164554	SCV002530202	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781744	SCV002550713	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486349	SCV002774687	uncertain significance	not provided	2022-09-26	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00028 (10/35434 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with suspected Lynch syndrome (PMID: 27601186 (2016)), however, the variant was noted to co-occur with a clearly pathogenic variant in a mismatch repair gene (PMIDs: 31433215 (2019), 26232782 (2015), and 25980754 (2015)). 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000411039	SCV004019797	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.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338434	SCV004048001	uncertain significance	Lynch syndrome 5		criteria provided, single submitter	clinical testing	The missense variant c.1559C>T (p.Ala520Val) in PMS2 gene has been reported in the literature in several affected individuals (Yurgelun et.al.,2015). This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ala520Val variant is reported with allele frequency of 0.007076% in gnomAD exomes and novel in gnomAD Exomes and 1000 Genomes. The amino acid Ala at position 520 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala520Val in PMS2 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance