Submissions for variant NM_000535.7(PMS2):c.1760G>A (p.Ser587Asn)

gnomAD frequency: 0.00001  dbSNP: rs762100304

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569664	SCV000663427	likely benign	Hereditary cancer-predisposing syndrome	2018-08-24	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	RCV000629864	SCV000750820	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine with asparagine at codon 587 of the PMS2 protein (p.Ser587Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. While this variant is present in population databases (rs762100304, ExAC), the frequency information is unreliable due to low sequence quality at this site. This variant has not been reported in the literature in individuals with a PMS2-related disease. The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function.  In addition, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000662639	SCV000785325	uncertain significance	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569664	SCV000903116	likely benign	Hereditary cancer-predisposing syndrome	2018-07-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821663	SCV002068732	uncertain significance	not specified	2019-04-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821663	SCV002500161	uncertain significance	not specified	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1760G>A (p.Ser587Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251242 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1760G>A has been reported in the literature in an individual affected with esophageal squamous cell carcinoma, however this individual also carried another missense variant in PMS2 (Deng_2019). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 2/53461 controls (Dorling_2021 through LOVD). The variant was also identified as a secondary finding in 3 of 572 ClinSeq participants who had atherosclerosis, but were not selected for personal or family history of cancer (Johnston_2012). 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: 30833958, 33471991, 22703879, 27600092). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (LB, n=3; VUS, n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000569664	SCV002530225	likely benign	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000569664	SCV004014920	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662639	SCV004019743	uncertain significance	Lynch syndrome 4	2023-04-03	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356078	SCV001551140	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The PMS2 p.Ser587Asn variant was identified in 3 of 1144 proband chromosomes (frequency: 0.003) in a screen of individuals with atherosclerosis for cancer-susceptibility genes; personal or family history of cancer was not required (Johnston 2012). The variant was also identified in dSNP (rs762100304) as "With Likely benign, Uncertain significance allele" and Clinvar (classified as likely benign by Ambry Genetics; and as uncertain significance by Invitae and Counsyl). The variant was identified in control databases in 1 of 30982 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017); observed in the Ashkenazi Jewish population in 1 of 302 chromosomes (freq: 0.003), while it was not observed in the European, African, Other, Latino, East Asian, European Finnish, or South Asian populations. The p.Ser587 residue is not conserved in mammals and 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.