ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1559C>T (p.Ala520Val) (rs63751300)

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Total submissions: 8
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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 In silico models in agreement (benign);Other strong data supporting benign classification;Structural Evidence
Invitae RCV000200307 SCV000254600 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 520 of the PMS2 protein (p.Ala520Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals with colorectal cancer and suspected Lynch syndrome (PMID: 27601186), including in cases where a pathogenic variant was also identified in a different mismatch repair gene (PMID: 25980754, 31433215). ClinVar contains an entry for this variant (Variation ID: 185185). An algorithm developed specifically for the PMS2 gene suggests that this missense change is likely to be tolerated (PMID: 22290698). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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 RCV000411039 SCV000488683 uncertain significance Hereditary nonpolyposis colorectal cancer type 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 Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc 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 uncertain significance not specified 2018-03-12 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 as well as an algorithm developed specifically for PMS2 (Ali, 2012). The variant allele was found at a frequency of 7.2e-05 in 20/277030 control chromosomes, predominantly in Latinos subcohort (10/34416 chrs tested). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.73 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. The c.1559C>T has been reported in the literature in several affected individuals, and co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.2210+1G>A; PMS2 c.1492del11), providing supporting evidence for a benign role (Yurgelun, 2015; Nomura, 2015). In addition, the variant has been reported as benign polymorphism (Balogh, 2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4 VUS, 1 likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286034 SCV001472552 likely benign none provided 2019-12-23 criteria provided, single submitter clinical testing

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