Submissions for variant NM_000535.7(PMS2):c.1771T>C (p.Cys591Arg)

dbSNP: rs764252217

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693132	SCV000820988	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 591 of the PMS2 protein (p.Cys591Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. 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 not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 571880). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their 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.
Color Diagnostics, LLC DBA Color Health	RCV000772031	SCV000904999	likely benign	Hereditary cancer-predisposing syndrome	2018-09-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001816711	SCV002068731	uncertain significance	not specified	2019-04-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000772031	SCV002530226	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	curation
Ambry Genetics	RCV000772031	SCV002711847	likely benign	Hereditary cancer-predisposing syndrome	2020-06-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358468	SCV001554210	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The PMS2 p.Cys591Arg variant was not identified in the literature. The variant was identified in dbSNP (ID: rs764252217), ClinVar (classified as uncertain significance by Invitae), and LOVD 3.0. The variant was identified in control databases in 1 of 246170 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Ashkenazi Jewish population in 1 of 9788 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, European, East Asian, Finnish, or South Asian populations. The p.Cys591 residue is not conserved in mammals and four out of five 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.
PreventionGenetics, part of Exact Sciences	RCV004742579	SCV005344659	uncertain significance	PMS2-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The PMS2 c.1771T>C variant is predicted to result in the amino acid substitution p.Cys591Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/571880/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.