7-5982885-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong
The NM_000535.7(PMS2):c.2113G>A(p.Glu705Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,604,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000264 AC: 4AN: 151518Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000398 AC: 9AN: 226056Hom.: 0 AF XY: 0.0000325 AC XY: 4AN XY: 123090
GnomAD4 exome AF: 0.0000145 AC: 21AN: 1452922Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9AN XY: 722454
GnomAD4 genome 0.0000264 AC: 4AN: 151518Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3AN XY: 73980
ClinVar
Submissions by phenotype
not provided Pathogenic:8
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Published functional studies demonstrate a damaging effect: defective homologous recombination and mismatch repair activities (Kadyrov et al., 2006; Erdeniz et al., 2007; Deschenes et al., 2007; Martinez et al., 2010; van Oers et al., 2010; Drost et al., 2013); Reportedly observed in the compound heterozygous state in a patient with constitutional mismatch repair deficiency in published literature (Lavoine et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26232782, 26945061, 16873062, 26110232, 27978560, 26318770, 32652087, 20624957, 22290698, 17029773, 18602922, 16619239, 17312306, 17567544, 18768816, 25512458, 22290424, 23612316, 16817031, 26704428, 9419979, 20176959, 24027009, 25430799, 26845104, 23012243, 26719141, 26681312, 27601186, 30809968, 31433215, 32642664, 30572730, 31992580, 31447099, 33453991, 33510387, 28888541, 30787465, 35189042, 35451682, 18619468) -
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PP4, PP5, PM3_supporting, PS3 -
The frequency of this variant in the general population, 0.000078 (9/114962 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals and families (PMID: 18602922 (2008), 27978560 (2016), 36134613 (2022)) affected with colorectal cancer (PMIDs: 16619239 (2006), 28466842 (2017), 30809968 (2019), 31433215 (2019), 31992580 (2020), 32652087 (2020), 33359728 (2022)) or a Lynch-syndrome-associated cancer (PMID: 23012243 (2013), 26681312 (2015), 23612316 (2013), 28888541 (2017)). The variant was also reported in a patient affected with CMMRD who had another variant in the PMS2 gene, although tumor testing showed a lack of both MLH1 and PMS2 proteins (PMID: 26318770 (2015)). Functional studies have shown that this variant causes defective DNA mismatch repair (PMIDs: 16873062 (2006), 17029773 (2007), 17567544 (2007), 20176959 (2010), 24027009 (2013), 33453991 (2020), 33510387 (2021), 35189042 (2022)). Based on the available information, this variant is classified as pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
The p.E705K variant (also known as c.2113G>A), located in coding exon 12 of the PMS2 gene, results from a G to A substitution at nucleotide position 2113. The glutamic acid at codon 705 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple patients with Lynch syndrome-associated malignancies, including tumors showing loss of PMS2 via immunohistochemistry and/or microsatellite instability (Miyaki M et al. Oncogene. 1997;15(23):2877-81; Senter L et al. Gastroenterology. 2008.135(2); 419-428; Miyaki M et al. Oncogene. 1997 Dec;15(23):2877-81; Lagerstedt Robinson K et al. J. Natl. Cancer Inst. 2007 Feb;99(4):291-9; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835; Haraldsdottir S et al. Nat Commun. 2017 May;8:14755, Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Thutkawkorapin J et al. Mol Genet Genomic Med, 2019 05;7:e605; Ambry internal data). This alteration has been detected in at least two individuals with features consistent with constitutional mismatch repair deficiency and had an additional PMS2 mutation (Lavoine et al. J. Med. Genet. 2015 Nov;52(11):770-8; Ambry internal data). In a functional study, the p.E705K variant inhibited mismatch repair activity in mammalian or yeast cells when it was expressed in excess amounts relative to the wild-type PMS2. However, it did not affect protein stability or its interaction with MLH1, suggesting that the p.E705K variant may behave in a recessive manner (Deschenes SM et al. Cancer Lett. 2007;249(2):148-56). In another functional study, analysis of this alteration in mice showed an increase in genomic mutation frequency and tumor incidence (van Oers JM et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Jul; 107(30):13384-9). In addition, this variant has been identified to have deficient function in several other assays (Ortega J et al. Cell Res, 2021 May;31:542-553; D'Arcy BM et al. Mol Genet Genomic Med, 2022 Feb;10:e1908). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
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This missense variant replaces glutamic acid with lysine at codon 705 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). The variant has been used as a non-functional control in a cell-free mismatch repair activity assay (PMID 24027009). It has also been shown to result in loss of PMS2 function in an endonuclease assay, a 6-thioguanine sensitivity assay and a mutator phenotype assay (PMID: 16873062, 17029773, 17567544). This variant has been detected in an individual affected with Turcot syndrome (PMID: 9419979), and in over ten individuals and families affected with Lynch syndrome-associated cancer (PMID: 16619239, 17312306, 18602922, 23612316, 26110232, 26681312, 26845104, 27601186, 27978560, 28466842, 30572730, 30809968). This variant also has been detected in an individual with a pathogenic covariant in PMS2 affected with biallelic constitutional mismatch repair deficiency syndrome (PMID: 26318770). This variant has been identified in 10/257172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Lynch syndrome 4 Pathogenic:3
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16873062, 20624957]. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Lynch syndrome 4, (MIM#614337) and mismatch repair cancer syndrome 4 (MIM#619101). (I) 0106 - This gene is associated with autosomal recessive disease. However, there is an additional dominant association to cancer (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with lynch syndrome may or may not be affected (PMID: 25856668). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated MutL_C domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic or pathogenic, and has been observed in individuals with mismatch repair deficiency and lynch syndrome-associated malignancies (ClinVar). (SP) 1207 - Parental origin of the variant is unresolved. As both parents are heterozygous for this variant, is it unclear who the variant was inherited from (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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Lynch syndrome Pathogenic:2
The p.Glu705Lys variant in PMS2 has been reported in 4 individuals with Lynch-related cancers (Miyaki 1997, Goldberg 2015, Susswein 2015, Pearlman 2017) and in a compound heterozygous individual with constitutional mismatch repair syndrome, in trans with c.[706?_903+?del] (Lavoine 2015). It has also been identified in 0.01% (9/114953) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 91328). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Martinez 2010, Drost 2013); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch Syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS3_Supporting, PS4_Supporting, PM3. -
This variant has been observed several times as one of two PMS2 variants in a patient with MSI high colon cancer (Clendenning 2006). In addition, this variant has been shown to affect mismatch repair in yeast models (Erdeniz 2007, Deschenes 2007). Several reports have documented consistent loss of PMS2 expression in the tumors of individuals with this variant (Clendenning 2006, Senter 2008, Moline 2013). Family studies provided evidence for segregation of this variant with MSI high cancer showing loss of PMS2 (internal laboratory data). There are too few reports of this variant to determine an independent estimate relative colon cancer risk for this variant. -
Breast and/or ovarian cancer Pathogenic:1
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PMS2-related disorder Pathogenic:1
The PMS2 c.2113G>A variant is predicted to result in the amino acid substitution p.Glu705Lys. This variant has been reported in multiple individuals with Lynch syndrome (see, for example, Clendenning et al. 2006. PubMed ID: 16619239; Senter et al. 2008. PubMed ID: 18602922; Vaughn et al. 2012. PubMed ID: 23012243; Lagerstedt-Robinson et al. 2016. PubMed ID: 27601186; Pearlman et al. 2017. PubMed ID: 27978560; Haraldsdottir et al. 2017. PubMed ID: 28466842; Okkels et al. 2019. PubMed ID: 31433215; Wang et al. 2020. PubMed ID: 31992580). This variant has also been reported in the compound heterozygous state in an individual with constitutional mismatch repair deficiency syndrome (Lavoine et al. 2015. PubMed ID: 26318770). Functional studies showed that this variant significantly affects homologous recombination and inhibits mismatch repair activities (Kadyrov et al. 2006. PubMed ID: 16873062; Martinez et al. 2010. PubMed ID: 20176959; Drost et al. 2013. PubMed ID: 24027009). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic/likely pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/91328/). This variant falls within a highly paralogous region. Allele frequency data should be interpreted with caution. This variant is interpreted as pathogenic. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: PMS2 c.2113G>A (p.Glu705Lys) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 226056 control chromosomes. c.2113G>A has been reported in the literature in multiple individuals affected with Turcot syndrome or Lynch Syndrome (e.g. Miyaki_1997, Haraldsdottir_2017, Okkels_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Martinez_2010, Drost_2013). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 705 of the PMS2 protein (p.Glu705Lys). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 16619239, 18602922, 23012243, 26110232, 26318770, 26681312, 26845104, 27601186, 27978560, 28466842; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 91328). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PMS2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 16873062, 17029773, 17567544, 20176959, 20624957, 24027009). For these reasons, this variant has been classified as Pathogenic. -
Lynch syndrome 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at