7-5982885-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E705D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1
• Conservation: PhyloP100: 7.90

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000535.7
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-5982883-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573081.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 7-5982885-C-T is Pathogenic according to our data. Variant chr7-5982885-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5982885-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2113G>A	p.Glu705Lys	missense_variant	12/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2113G>A	p.Glu705Lys	missense_variant	12/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151518 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 9 AN: 226056 Hom.: 0 AF XY: 0.0000325 AC XY: 4 AN XY: 123090

Gnomad AFR exome AF: 0.0000768

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000803

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 21 AN: 1452922 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 722454

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151518 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3 AN XY: 73980

Gnomad4 AFR AF: 0.0000487

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000743 AC: 9

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 29, 2022	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. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 25, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 09, 2023	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. -

Lynch syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 13, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Mar 25, 2016	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. -

Lynch syndrome 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 13, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 21, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16873062, 20624957]. -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 09, 2022

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 22, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

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; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 91328). 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 expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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

Uncertain significance, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;.;D;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D;D;.;.;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.97
MVP		0.95
MPC		3.5
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608161; hg19: chr7-6022516;