rs200313585

Positions:

chr7-6004042-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000535.7(PMS2):c.180C>G(p.Asp60Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,586,516 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D60N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 2 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:19

Conservation

PhyloP100: -0.140

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013067961).

BP6

Variant 7-6004042-G-C is Benign according to our data. Variant chr7-6004042-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 91315.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-6004042-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000855 (130/151978) while in subpopulation NFE AF= 0.000794 (54/68026). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.180C>G	p.Asp60Glu	missense_variant	3/15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.180C>G	p.Asp60Glu	missense_variant	3/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.000855

AC:

130

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00615

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000915

AC:

229

AN:

250142

Hom.:

AF XY:

0.000879

AC XY:

119

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00628

Gnomad NFE exome

AF:

0.000716

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000717

AC:

1029

AN:

1434538

Hom.:

Cov.:

AF XY:

0.000664

AC XY:

475

AN XY:

715236

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00616

Gnomad4 NFE exome

AF:

0.000602

Gnomad4 OTH exome

AF:

0.000607

GnomAD4 genome

AF:

0.000855

AC:

130

AN:

151978

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00615

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.000731

Hom.:

Bravo

AF:

0.000359

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00101

AC:

123

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS2 p.Asp60Glu variant was identified in 2 of 792 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (van der Klift 2016). The variant was also identified in the following databases: dbSNP (ID: rs200313585) as "With Likely benign allele", ClinVar (4x likely benign, including review by expert panel InSiGHT, 1x benign), Clinvitae, and Insight Hereditary Tumors Database (6x, likely not pathogenic/little clinical significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 271 of 276504 chromosomes (2 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 4 of 24012 chromosomes (freq: 0.0002), Other in 13 of 6456 chromosomes (freq: 0.002), Latino in 2 of 34384 chromosomes (freq: 0.00006), European in 95 of 126292 chromosomes (freq: 0.0008), and Finnish in 157 of 25784 chromosomes (freq: 0.006). The variant was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. A functional study utilizing a cell-free assay found c.180C>G in vitro mismatch repair activity conserved (Drost 2013). Another study investing the splicing pattern of c.180C>G through use of a minigene assay found no aberrant splicing (van der Klift 2015). The p.Asp60 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 24, 2021	- -
Likely benign, 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 27, 2023	Variant summary: PMS2 c.180C>G (p.Asp60Glu) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00095 in 281538 control chromosomes, predominantly at a frequency of 0.00075 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11 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 Non-Finnish European origin. However, this data must be interpreted with caution as there is high homology to a pseudogene, which may artificially inflate the allele frequency. c.180C>G has been reported in the literature in individuals affected with Lynch Syndrome or prostate cancer (Grant_2015, van der Klift_2016, Mateo_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Functional studies showed that this variant was not associated with aberrant splicing (van der Klift_2015) and MMR efficiency at 70% of the wild-type levels (Drost_2013). Multiple ClinVar submissions (evaluation after 2014) cite the variant as benign and likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	This variant is associated with the following publications: (PMID: 26247049, 24027009, 26336887, 27435373) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PMS2: BP1, BS3:Supporting -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 27, 2025	The missense variant NM_001322014.2(PMS2):c.180C>G (p.Asp60Glu) has been reported to ClinVar as Likely benign with a status of (3 stars) reviewed by expert panel (Variation ID 91315 as of 2025-01-02). There is a small physicochemical difference between aspartic acid and glutamic acid, which is not likely to impact secondary protein structure as these residues share similar properties. The p.Asp60Glu variant is not predicted to disrupt the existing acceptor splice site The p.Asp60Glu missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The glutamic acid residue at codon 60 of PMS2 is present in Domestic goat and 4 other mammalian species. The nucleotide c.180 in PMS2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 28, 2020	- -

Lynch syndrome 4

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 27, 2019

- -

Lynch syndrome

Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

-0.011

MutationAssessor

Benign

-0.12

N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.63

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.022

B;D

Vest4

0.37

MutPred

0.30

Loss of ubiquitination at K57 (P = 0.0997);Loss of ubiquitination at K57 (P = 0.0997);

MVP

0.91

MPC

0.042

ClinPred

0.0074

GERP RS

1.3

Varity_R

0.11

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over