7-5999193-C-T

Variant names:

• chr7-5999193-C-T
• rs374704824
• NM_000535.7:c.620G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000535.7(PMS2):​c.620G>A​(p.Gly207Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00022 in 1,613,928 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G207R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:10
• Conservation: PhyloP100: 4.64
• Publications: 21 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09531981).
• BP6: Variant 7-5999193-C-T is Benign according to our data. Variant chr7-5999193-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127793.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000197 (30/152192) while in subpopulation SAS AF = 0.00207 (10/4826). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.620G>A	p.Gly207Glu	missense	Exon 6 of 15	NP_000526.2
	PMS2	NM_001406866.1		c.806G>A	p.Gly269Glu	missense	Exon 7 of 16	NP_001393795.1
	PMS2	NM_001322014.2		c.620G>A	p.Gly207Glu	missense	Exon 6 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.620G>A	p.Gly207Glu	missense	Exon 6 of 15	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.620G>A	p.Gly207Glu	missense	Exon 6 of 11	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.620G>A		non_coding_transcript_exon	Exon 6 of 13	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000374 AC: 94 AN: 251494 AF XY: 0.000478

Gnomad AFR exome AF: 0.0000615

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: 0.000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000222 AC: 325 AN: 1461736 Hom.: 2 Cov.: 33 AF XY: 0.000300 AC XY: 218 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00191 AC: 165 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111954

Other (OTH) AF: 0.000182 AC: 11 AN: 60390

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74414

African (AFR) AF: 0.0000241 AC: 1 AN: 41534

American (AMR) AF: 0.000262 AC: 4 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3 Benign:1

Mar 07, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.620G>A (p.Gly207Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutL domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The nucleotide sequence surrounding this genomic location is unique to PMS2 and not found in the psuedogene, thus identification of this variant in patients and controls is expected to truly be in the PMS2 gene. The variant allele was found at a frequency of 0.00037 in 251990 control chromosomes, predominantly at a frequency of 0.002 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.620G>A has been reported in the literature in individuals affected with Lynch Syndrome, Breast/Ovarian Cancers (example, Montazer Haghighi_2009, Maxwell_2014, Warren_2015, Goldescu_2018, Lu_2015, Siraj_2017, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Co-occurrences with other pathogenic variant(s) have been reported in the literature and observed at our laboratory (Tung_2015, ATM c.1564_1565del , p.Glu522Ilefs*43; our laboratory, BRCA1 c.5266dupC, p.Q1756fs*74; CHEK2 c.1100delC, p.Thr367fs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in mildly defective in MMR activity (~70% of wild type activity; Drost_2013), with activity significantly higher than the repair deficient control. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign, n=4, likely benign, n=1, VUS, n=6). Many submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging consensus towards a neutral outcome as evidence outlined above, the variant was classified as benign.

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified as DM in HGMD and has been seen in one person with colorectal cancer. It is present in gnomAD at a Max MAF of 0.19% (61/30900 South Asian chrs - too high for disease incidence). It is classified in ClinVar with 1 star as VUS by GeneDx, Ambry, and CSER_CC_NCGL, and as Likely Benign by Invitae.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 24, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.620G>A, in exon 6 that results in an amino acid change, p.Gly207Glu. This sequence change has been described in the gnomAD database with a global population frequency of 0.03% and up to a 0.2% frequency in certain subpopulations (dbSNP rs374704824). The p.Gly207Glu change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly207Glu substitution. The p.Gly207Glu change has been reported in a patient with hereditary non-polyposis colorectal cancer and tumor testing showing absence of PMS2 expression and high microsatellite instability (PMID: 19479271). The p.Gly207Glu change has also been reported in a patient with breast cancer (PMID: 25503501). Functional studies using an in vitro assay demonstrated normal mismatch repair activity (PMID: 24027009). Due to these contrasting evidences, the clinical significance of the p.Gly207Glu change remains unknown at this time.

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Jul 02, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

Jul 07, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Jul 07, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1 Benign:2

Jun 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31992580, 30653781, 31159747, 30651582, 26689913, 29785153, 28975465, 25503501, 19479271, 24027009, 25637381)

Dec 13, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 24, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lynch syndrome 4 Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 27, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

Polyp of colon Uncertain:1

Jul 01, 2015

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 24 year old female with a personal history of 11-20 colon polyps and family history of colorectal cancer and/or polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.

Breast and/or ovarian cancer Uncertain:1

Dec 23, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Endometrial carcinoma Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Gly207Glu variant was identified in 1 of 1184 proband chromosome (frequency: 0.0008) from individuals or families with Hereditary Non-Polyposis Colorectal Cancer and was not identified in 496 control chromosomes from healthy individuals (Montazer Haghighi 2009). In the same publication the patient who carried the p.Gly207Glu variant had a tumor that was negative for PMS2 IHC but was MSI-high suggesting that the variant may have clinical significance (Montazer Haghighi 2009). The variant was also identified in dbSNP (ID: rs374704824 as "With Uncertain significance, other allele"), ClinVar (6x as uncertain significance and 2x as likely benign), Cosmic (as a somatic mutation in squamous cell carcinoma), and Insight Hereditary Tumors Database (as Unknown). The variant was not identified in MutDB, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 96 of 277222 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), European Non-Finnish in 33 of 126724 chromosomes (freq: 0.0003), and South Asian in 62 of 30782 chromosomes (freq: 0.002) and was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. An in vitro assay showed that a recombinant protein with the p.Gly207Glu variant was positive for MMR activity also suggesting that the variant does not have clinical significance (Drost 2013). The p.Gly207 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not reliably predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, given the conflicting evidence, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

PMS2-related disorder Benign:1

Aug 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.095	T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.011	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.65
MVP		0.89
MPC		0.26
ClinPred		0.34	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.67
Mutation Taster		=4/96	disease causing

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: rs374704824; hg19: chr7-6038824; COSMIC: COSV56224587; COSMIC: COSV56224587;