Submissions for variant NM_000535.7(PMS2):c.241G>A (p.Glu81Lys)

gnomAD frequency: 0.00001  dbSNP: rs730881919

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160904	SCV000211600	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including endometrial, pancreatic, and breast/ovarian cancer, as well as in cancer-free controls (Goodfellow et al., 2015; Cock-Rada et al., 2018; Mizukami et al., 2020; Wang et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26552419, 28528518, 31992580, 32980694, 35980372, 33471991, 11574484)
Invitae	RCV000206458	SCV000260529	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 81 of the PMS2 protein (p.Glu81Lys). This variant is present in population databases (rs730881919, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, endometrial cancer, ovarian cancer, and/or pancreatic cancer (PMID: 26552419, 28528518, 31992580, 32980694). ClinVar contains an entry for this variant (Variation ID: 182817). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function. 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.
Ambry Genetics	RCV000575606	SCV000663434	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The p.E81K variant (also known as c.241G>A), located in coding exon 3 of the PMS2 gene, results from a G to A substitution at nucleotide position 241. The glutamic acid at codon 81 is replaced by lysine, an amino acid with similar properties. This alteration has been reported multiple individuals with endometrial cancer (Goodfellow PJ et al. J Clin Oncol. 2015 Dec 20;33(36):4301-8; Wang Q et al. J Med Genet, 2020 07;57:487-499). This alteration was detected in a cohort of unrelated Brazilian individuals with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363), and has also been reported in conjunction with a pathogenic PALB2 mutation in a patient meeting hereditary breast/ovarian cancer testing guidelines (Cock-Rada AM et al. Fam Cancer. 2017 May 20). This variant was reported with a carrier frequency of 0.001 in 1005 Japanese pancreatic cancer patients and 0.00004 in 23705 controls of Japanese ancestry (Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575606	SCV000691061	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 81 of the PMS2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer that exhibited microsatellite instability (PMID: 26552419), an individual affected with pancreatic cancer (PMID: 32980694), in individuals affected with breast or ovarian cancer (PMID: 28528518, 33471991), as well as in unaffected individuals (PMID: 32980694, 33471991). This variant has been identified in 4/250820 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in a healthy control individual (PMID: 32980694). 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.
Counsyl	RCV000662544	SCV000785124	uncertain significance	Lynch syndrome 4	2017-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781760	SCV000920058	uncertain significance	not specified	2018-12-18	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.241G>A (p.Glu81Lys) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal and Histidine kinase/HSP90-like ATPase domains of 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 1.6e-05 in 245818 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.241G>A, has been reported in the literature in individuals affected with HBOC (Cock-Rada_2017, Goodfellow_2015). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (PALB2 c.1240C>T, p.Arg414X), providing supporting evidence for a benign role. In addition, one patient was indicated to have IHC defects consistent with an MSH2 mutation (absent MSH2 and MSH6)(Goodfellow_2015)To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160904	SCV001134593	uncertain significance	not provided	2018-11-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575606	SCV002530305	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-02	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000160904	SCV003811208	uncertain significance	not provided	2019-05-22	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000662544	SCV003936825	uncertain significance	Lynch syndrome 4	2023-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 81 of the PMS2 protein (p.Glu81Lys). This variant is present in population databases (rs730881919, gnomAD 0.006%). This missense change has been observed in individual(s) with endometrial cancer, breast and/or ovarian cancer (PMID: 26552419, 28528518, 31992580). ClinVar contains an entry for this variant (Variation ID: 182817) by 7 submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. This amino acid position is well conserved in available vertebrate species. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at diagnostic lab indicates that this missense variant is not expected to disrupt PMS2 protein function. 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315414	SCV004015235	uncertain significance	Mismatch repair cancer syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 81 of the PMS2 protein (p.Glu81Lys). This variant is present in population databases (rs730881919, gnomAD 0.006%). This missense change has been observed in individual(s) with endometrial cancer, breast and/or ovarian cancer (PMID: 26552419, 28528518, 31992580). ClinVar contains an entry for this variant (Variation ID: 182817) by 7 submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. This amino acid position is well conserved in available vertebrate species. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at diagnostic lab indicates that this missense variant is not expected to disrupt PMS2 protein function. 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.
Myriad Genetics, Inc.	RCV000662544	SCV004019847	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.
Baylor Genetics	RCV000662544	SCV004205373	uncertain significance	Lynch syndrome 4	2023-10-19	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000575606	SCV004228121	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998530	SCV004842140	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 81 of the PMS2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer that exhibited microsatellite instability (PMID: 26552419), an individual affected with pancreatic cancer (PMID: 32980694), in individuals affected with breast or ovarian cancer (PMID: 28528518, 33471991), as well as in unaffected individuals (PMID: 32980694, 33471991). This variant has been identified in 4/250820 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in a healthy control individual (PMID: 32980694). 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.