7-5982885-C-T

Variant names:

• chr7-5982885-C-T
• rs267608161
• NM_000535.7:c.2113G>A

Variant summary

Our verdict is Pathogenic. The variant received 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:23 U:1
• Conservation: PhyloP100: 7.90
• Publications: 29 publications found

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]

PMS2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 49 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 VariationId is 573081.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 91328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.2113G>A	p.Glu705Lys	missense	Exon 12 of 15	NP_000526.2
	PMS2	NM_001406866.1		c.2299G>A	p.Glu767Lys	missense	Exon 13 of 16	NP_001393795.1
	PMS2	NM_001322014.2		c.2113G>A	p.Glu705Lys	missense	Exon 12 of 15	NP_001308943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2113G>A	p.Glu705Lys	missense	Exon 12 of 15	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.910G>A	p.Glu304Lys	missense	Exon 8 of 11	ENSP00000371758.4
	PMS2	ENST00000469652.1	TSL:1	n.83G>A		non_coding_transcript_exon	Exon 3 of 3

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

GnomAD2 exomes AF: 0.0000398 AC: 9 AN: 226056 AF XY: 0.0000325

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 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

African (AFR) AF: 0.0000302 AC: 1 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 43828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4400

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1107354

Other (OTH) AF: 0.0000334 AC: 2 AN: 59928

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000487 AC: 2 AN: 41068

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0188335), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000743 AC: 9

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 29, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Feb 14, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PP5, PM3_supporting, PS3

Feb 18, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:4

Jan 25, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Sep 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Tumor data from many affected individuals has displayed high microsatellite instability and/or loss or PMS2 protein expression via immunohistochemistry (PMID: 16619239, 16817031, 18602922, 23612316, 26318770, 30572730, 30809968). This variant has been identified in 10/257172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequence in the PMS2CL pseudogene. Based on the available evidence, this variant is classified as Pathogenic.

Dec 16, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 20, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP3_Moderate, PP4_Strong c.2113G>A, located in exon 12 of the PMS2 gene (C-terminal endonuclease domain) is predicted to result in the substitution of Acid Glutamic by Lysine at codon 705, p.(Glu705Lys). This variant is found in 25/1604440 alleles (0.0015%) in the gnomAD v4.1.0 database, with a maximal credible allele frequency of 0.0011% (no criterion is met). The SpliceAI algorithm predicts no significant impact on splicing. Computational tools predict a deleterious effect of the variant on protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0,86) (PP3_Moderate). MMR assays have shown that the variant completely suppresses MMR activity (odds of pathogenicity = 32.93; PMID: 24027009; 17029773; 35189042) (PS3). PMS2 c.2113G>A variant has been identified in a patient affected with Turcot syndrome (PMID: 9419979) and in multiple CRC patients whose tumors showed loss of PMS2 expression (PMID 16619239, 17312306, 18602922, among others) (PP4_Moderate). Additionally, it has also been reported co-ocurring with another PMS2 variant in a child with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (PM3 is not applied because PM2 is not fullfilled) (PMID: 26318770). c.2113G>A has been reported in the ClinVar database (1x uncertain significance, 6x likely pathogenic, 14x pathogenic) and in the LOVD database (16x uncertain significance, 3x pathogenic and 3 NA). It has been reported in the InSiGHT database as an uncertain significance variant (Classification Date: 2013/09/05 v1.9). At present ClinVar decribes two other missense variants in the same residue, c.2114A>G, p.(Glu705Gly), classified as a likely pathogenic variant (1x without functional evidence data), and variant c.2115G>C, p.(Glu705Asp), classified as uncertain significance (2x) and pathogenic (1x). Based on the currently available information, c.2113G>A is classified as a pathogenic variant according to ClinGen_CRC_ACMG_Specifications_PMS2_v1.0.0.

Lynch syndrome 4 Pathogenic:3

Sep 21, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16873062, 20624957].

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lynch syndrome Pathogenic:2

May 13, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 25, 2016

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Jul 29, 2025

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PS3, PS4_M, PM1, PM2_P, PM3, PP3, PP4, PP5; Variant was found in heterozygous state in Proband.

Breast and/or ovarian cancer Pathogenic:1

Mar 09, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2-related disorder Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Sep 22, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1

Nov 13, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lynch syndrome 1 Uncertain:1

Jul 24, 2014

Pathway Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	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
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267608161; hg19: chr7-6022516;