7-6005996-C-T

Variant names:

• chr7-6005996-C-T
• rs10254120
• NM_000535.7:c.59G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.59G>A​(p.Arg20Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 1,610,336 control chromosomes in the GnomAD database, including 4,147 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.074 (450 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3697 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:23 O:1
• Conservation: PhyloP100: 0.288
• Publications: 57 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026167035).
• BP6: Variant 7-6005996-C-T is Benign according to our data. Variant chr7-6005996-C-T is described in ClinVar as Benign. ClinVar VariationId is 41716.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.59G>A	p.Arg20Gln	missense_variant	Exon 2 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.59G>A	p.Arg20Gln	missense_variant	Exon 2 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11312 AN: 152042 Hom.: 448 Cov.: 32

Gnomad AFR AF: 0.0899

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.0956

Gnomad SAS AF: 0.0899

Gnomad FIN AF: 0.0871

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0681

Gnomad OTH AF: 0.0786

GnomAD2 exomes AF: 0.0716 AC: 17574 AN: 245616 AF XY: 0.0727

Gnomad AFR exome AF: 0.0904

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0418

Gnomad EAS exome AF: 0.0954

Gnomad FIN exome AF: 0.0832

Gnomad NFE exome AF: 0.0756

Gnomad OTH exome AF: 0.0646

GnomAD4 exome AF: 0.0684 AC: 99812 AN: 1458176 Hom.: 3697 Cov.: 32 AF XY: 0.0692 AC XY: 50206 AN XY: 725440

African (AFR) AF: 0.0887 AC: 2962 AN: 33400

American (AMR) AF: 0.0272 AC: 1216 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0391 AC: 1022 AN: 26124

East Asian (EAS) AF: 0.0907 AC: 3598 AN: 39684

South Asian (SAS) AF: 0.0886 AC: 7638 AN: 86160

European-Finnish (FIN) AF: 0.0895 AC: 4681 AN: 52276

Middle Eastern (MID) AF: 0.0537 AC: 222 AN: 4136

European-Non Finnish (NFE) AF: 0.0668 AC: 74263 AN: 1111498

Other (OTH) AF: 0.0700 AC: 4210 AN: 60184

GnomAD4 genome AF: 0.0744 AC: 11314 AN: 152160 Hom.: 450 Cov.: 32 AF XY: 0.0754 AC XY: 5605 AN XY: 74378

African (AFR) AF: 0.0898 AC: 3727 AN: 41506

American (AMR) AF: 0.0489 AC: 747 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3468

East Asian (EAS) AF: 0.0956 AC: 495 AN: 5176

South Asian (SAS) AF: 0.0891 AC: 430 AN: 4824

European-Finnish (FIN) AF: 0.0871 AC: 922 AN: 10580

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0681 AC: 4632 AN: 68028

Other (OTH) AF: 0.0778 AC: 164 AN: 2108

Alfa AF: 0.0693 Hom.: 118

Bravo AF: 0.0705

TwinsUK AF: 0.0574 AC: 213

ALSPAC AF: 0.0623 AC: 240

ESP6500AA AF: 0.0906 AC: 246

ESP6500EA AF: 0.0592 AC: 272

ExAC AF: 0.0775 AC: 9036

Asia WGS AF: 0.0840 AC: 290 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:23 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7 Other:1

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg20Gln in exon 2 of PMS2: This variant is not expected to have clinical sign ificance because it has been identified in 7.8% (9003/115162) of total chromosom es by the Exome Aggregation Consortium (ExAC), including 410 homozygous individu als (http://exac.broadinstitute.org; dbSNP rs10254120). Furthermore, it was clas sified as benign on Sep. 5, 2013 by the ClinGen-approved InSiGHT expert panel (C linVar SCV000108372.2). -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 4 Benign:6

Jan 23, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28932927, 24728327, 26811195, 27153395, 7704024, 27884173, 8072530, 18768816, 24689082, 24618965, 22949387, 21239990, 23981578, 22703879) -

Lynch syndrome Benign:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Oct 01, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Nov 05, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Lynch syndrome 1 Benign:1

Jul 24, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Endometrial carcinoma Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PMS2, EXON 2, c.59G>A, p.Arg20Gln, Benign (ACMG 5) In the (8072530_Nicolaides_1994, 16472587_Hendriks_2006 , 18768816_Marionvic-Terzic_2008 21239990_Pastrello_2011 , 22703879_Johnston_2012 , 23709753_Borras_2013 23981578_Wang_2013, 24618965_Dewey_2014, 24689082_Hansen_2014, 24728327_Bodian_2014, 22949387_Thompson_2013) articles, a total of 8 proband alleles of 112 (frequency: 0.027) tested positive for the variant and of the controls a total of 31 alleles of 379 tested positive (frequency: 0.082). In 22703879_johnston_2012, the variant was found in 77 of 572 individuals not included in the previous numbers; many of the articles suggest that the variant is a polymorphism and is benign. The variant was also identified in dbSNP (ID: rs10254120 ) “With untested allele”, with a minor allele frequency of 7.024% (1000 Genomes Project), HGMD, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, ClinVar database. In the ClinVar database, 5 separate submitters classify the variant as benign. This variant was identified in the 1000 Genomes Project in 153 of 2178 chromosomes (frequency: 0.07), Exome Variant Server project in 272 of 4320 European American (frequency: 0.06) and in 246 of 2714 African American alleles (frequency: 0.09), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Arg20 residue is not conserved in mammals and the variant amino acid Glycine (Gly) is present in Trichoplax adhaerens, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The c.59G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.84	T;D
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.0	M;M
PhyloP100		0.29
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.12	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.50	P;P
Vest4		0.15
MPC		0.043
ClinPred		0.015	T
GERP RS		0.77
Varity_R		0.036
gMVP		0.22
Mutation Taster		=97/3	polymorphism (auto)

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: rs10254120; hg19: chr7-6045627; COSMIC: COSV56151364; COSMIC: COSV56151364;