7-5999193-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

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. G207A) 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:9 B:8
• Conservation: PhyloP100: 4.64

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 Likely_benign. Variant got -3 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 id is 127793.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Benign=5, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.620G>A	p.Gly207Glu	missense_variant	6/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.620G>A	p.Gly207Glu	missense_variant	6/15	1	NM_000535.7	P3

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

GnomAD3 exomes AF: 0.000374 AC: 94 AN: 251494 Hom.: 0 AF XY: 0.000478 AC XY: 65 AN XY: 135920

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 SAS exome AF: 0.00203

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.000182

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 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:9 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 24, 2020	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

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 07, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 07, 2021	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 24, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2020	This variant is associated with the following publications: (PMID: 31992580, 30653781, 31159747, 30651582, 26689913, 29785153, 28975465, 25503501, 19479271, 24027009, 25637381) -

Polyp of colon Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jul 01, 2015

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 23, 2022

- -

PMS2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2023

The PMS2 c.620G>A variant is predicted to result in the amino acid substitution p.Gly207Glu. This variant has been reported in individuals with hereditary nonpolyposis colorectal cancer (Montazer Haghighi et al. 2009. PubMed ID: 19479271), breast cancer (Siraj et al. 2017, Table S4. PubMed ID: 28975465) and in at least one individual with no history of cancer (Amendola et al. 2015, Table S1. PubMed ID: 25637381). An in vitro study on this variant showed it still retained DNA mismatch repair (MMR) activity (Drost et al. 2013. PubMed ID: 24027009). This variant is reported in 0.20% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6038824-C-T) and has conflicting interpretations of benign, likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127793/). Although we suspect that this variant may be benign at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Endometrial carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Lynch syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.095	T;T;T;T;T;T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D;D;.;.;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.011	D;D;.;.;.;T
Sift4G	Benign	0.12	T;T;.;.;.;T
Polyphen		1.0	D;D;.;.;D;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

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