rs63750668

chr7-5987077-C-Achr7-5987077-C-Gchr7-5987077-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000535.7(PMS2):c.1688G>T(p.Arg563Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00817 in 1,614,018 control chromosomes in the GnomAD database, including 66 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. R563Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (63 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:35 O:1
• Conservation: PhyloP100: -0.0260

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 Benign. Variant got -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000535.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.006866634).
• BP6: Variant 7-5987077-C-A is Benign according to our data. Variant chr7-5987077-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 41705.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5987077-C-A is described in Lovd as [Likely_benign]. Variant chr7-5987077-C-A is described in Lovd as [Benign]. Variant chr7-5987077-C-A is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1688G>T	p.Arg563Leu	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1688G>T	p.Arg563Leu	missense_variant	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 1033 AN: 152116 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00973

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00628 AC: 1578 AN: 251182 Hom.: 3 AF XY: 0.00629 AC XY: 854 AN XY: 135790

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.00642

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00670

Gnomad NFE exome AF: 0.00894

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00831 AC: 12154 AN: 1461784 Hom.: 63 Cov.: 32 AF XY: 0.00824 AC XY: 5990 AN XY: 727216

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00689

Gnomad4 ASJ exome AF: 0.00570

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00704

Gnomad4 NFE exome AF: 0.00944

Gnomad4 OTH exome AF: 0.00866

GnomAD4 genome AF: 0.00680 AC: 1035 AN: 152234 Hom.: 3 Cov.: 32 AF XY: 0.00684 AC XY: 509 AN XY: 74442

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00837

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00973

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00864 Hom.: 14

Bravo AF: 0.00708

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00581 AC: 705

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:35 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 4 Uncertain:1 Benign:8

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 11, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 04, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 19, 2018	- -

not provided Benign:8

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PMS2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:7 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	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: No convincing evidence in HGMD, ExAC: 0.8% (541/66472) European chromosomes -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 19, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 08, 2017	- -

Lynch syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 20, 2015	- -
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 -

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

Apr 13, 2021

- -

Lynch syndrome 1 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Sep 12, 2022

This variant has been reported in association with cancer (Clendenning 2006 PMID: 16619239). This variant is present in the Genome Aggregation Database (Highest reported MAF: 1.0% [157/15246], and in 3 homozygotes; https://gnomad.broadinstitute.org/variant/7-5987077-C-A?dataset=gnomad_r3). This variant is also present in ClinVar, with numerous laboratories classifying it as benign or likely benign, including as likely benign by the InSiGHT expert panel (Variation ID: 41705). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, this variant is classified as benign. -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

PMS2, EXON 11, c.1688G>T, p. Arg563Leu, Benign (ACMG 5) The PMS2 p.Arg563Leu variant was identified in 5 of 416 proband chromosomes (frequency: 0.012) from individuals or families with Lynch Syndrome (16472587_Hendriks_2006, 16619239_Clendenning_2006, 24027009_Drost_2014, 24689082_Hansen_2014). The variant was also identified in dbSNP (ID: rs63750668) “With likely benign, uncertain significance allele”, with a minor allele frequency of 0.003 (1000 Genomes Project), HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, and “InSiGHT Colon Cancer Database”. The variant was classified as a benign/likely benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The variant was classified as “unclassified” by a clinical laboratory within the Canadian Open Genetics Repository (http://opengenetics.ca/). This variant was identified in the 1000 Genomes Project in 17 of 2178 chromosomes (frequency: 0.0014), and Exome Variant Server project in 86 of 8600 European American (frequency: 0.01) and 18 of 4406 African American alleles (frequency: 0.004), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Arg563 residue is not conserved in mammals and the variant amino acid Leucine (Leu) is present in Ciona intestinalis, increasing the likelihood that this variant does not have clinical significance. The p.Arg563 residue is not conserved in mammals and 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. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The DNA NOMENCLATURE 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	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	6.5
Dann	Benign	0.93
DEOGEN2	Benign	0.14	T;.;.;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.70	T;T;.;T;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0069	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.9	N;N;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.34	T;T;.;.;.
Sift4G	Benign	0.28	T;T;.;.;.
Polyphen		0.029	B;P;.;.;P
Vest4		0.41
MVP		0.52
MPC		0.050
ClinPred		0.0079	T
GERP RS		-0.27
Varity_R		0.069
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750668; hg19: chr7-6026708; COSMIC: COSV56221604;