7-5997349-G-C

Position:

• chr7-5997349-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000535.7(PMS2):​c.780C>G​(p.Ser260Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,588,048 control chromosomes in the GnomAD database, including 527,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S260S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.82 (50628 hom., cov: 27)
  • Exomes 𝑓: 0.81 (476522 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Benign reviewed by expert panel B:23
• Conservation: PhyloP100: -2.26

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-5997349-G-C is Benign according to our data. Variant chr7-5997349-G-C is described in ClinVar as [Benign]. Clinvar id is 36693.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5997349-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.780C>G	p.Ser260Ser	synonymous_variant	7/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.780C>G	p.Ser260Ser	synonymous_variant	7/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.817 AC: 123495 AN: 151176 Hom.: 50590 Cov.: 27

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.815

GnomAD3 exomes AF: 0.802 AC: 200814 AN: 250454 Hom.: 81226 AF XY: 0.808 AC XY: 109330 AN XY: 135374

Gnomad AFR exome AF: 0.842

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.921

Gnomad SAS exome AF: 0.817

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.817

Gnomad OTH exome AF: 0.804

GnomAD4 exome AF: 0.813 AC: 1168257 AN: 1436754 Hom.: 476522 Cov.: 27 AF XY: 0.815 AC XY: 583562 AN XY: 716378

Gnomad4 AFR exome AF: 0.842

Gnomad4 AMR exome AF: 0.662

Gnomad4 ASJ exome AF: 0.835

Gnomad4 EAS exome AF: 0.930

Gnomad4 SAS exome AF: 0.816

Gnomad4 FIN exome AF: 0.798

Gnomad4 NFE exome AF: 0.814

Gnomad4 OTH exome AF: 0.823

GnomAD4 genome AF: 0.817 AC: 123582 AN: 151294 Hom.: 50628 Cov.: 27 AF XY: 0.815 AC XY: 60150 AN XY: 73808

Gnomad4 AFR AF: 0.843

Gnomad4 AMR AF: 0.736

Gnomad4 ASJ AF: 0.849

Gnomad4 EAS AF: 0.914

Gnomad4 SAS AF: 0.812

Gnomad4 FIN AF: 0.794

Gnomad4 NFE AF: 0.812

Gnomad4 OTH AF: 0.818

Alfa AF: 0.810 Hom.: 12617

Bravo AF: 0.812

Asia WGS AF: 0.835 AC: 2906 AN: 3478

EpiCase AF: 0.815

EpiControl AF: 0.818

ClinVar

Significance: Benign

Submissions summary: Benign:23

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2014	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2017	p.Ser260Ser in exon 7 of PMS2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 92% (17375/18832) o f East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs1805319). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Lynch syndrome 4 Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -

Lynch syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Mismatch repair cancer syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ser260Ser variant was identified in 13 of 82 proband chromosomes (frequency: 0.159) from individuals or families with endometrial or colorectal cancer (Clendenning, 2006); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. This mutation was found in conjunction with several other mutations and had normal MLPA results for PMS2 and negative immunohistochemistry (IHC) staining for PMS2. It was not predicted to be deleterious or putatively deleterious. The p.Ser260Ser variant was identified in 9 of 76 proband chromosomes (frequency: 0.12) from individuals or families with predicted HNPCC (Hendriks, 2006); However, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. This mutation had 1 of 8 cases with negative PMS2 IHC staining. Nakagawa (2004) identified 2 of 14 proband chromosomes (frequency.0.15) from individuals with consecutively diagnosed endometrial or colorectal cancer in Ohio. All tumours stained positive for MSH2, MSH6 and MLH1 and negative staining for PMS2. All tumours identified were microsatellite instability (MSI) positive. A dissertation by Niessen identified 21 of 146 probands (frequency: 0.14() in individuals with colorectal cancer, early onset endometrial cancer or HNPCCC-associated tumours. 2 of 13 tested cases had negative PMS2 IHC staining and the mutation was classified as likely non-pathogenic or as a polymorphism. The patients had no germ-line mutations in MSH2, MSH6 or MLH1 and had at least 1 MSI positive tumour. Trondheim’s dissertation (2013) identified the p.Ser260Ser in 33 heterozygous and 82 homozygous cases of 238 proband chromosomes (0.828) in individuals with suspected HNPCC; however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was classified as non-pathogenic or of no clinical significance by the authors. This variant was identified in the 1000 Genomes Project in 56 of 342 chromosomes (frequency: 0.15), with prevalence in the PUR, CLM, MXL populations. Exome Variant Server project identified the variant in 1593 of 8600 European American and 699 of 4406 African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Ser260Ser variant has been identified in the InSiGHT Colon Cancer Database and in ClinVar. It was identified by the Emory Genetics Laboratory and is classified as no known pathogenicity and highly penetrant. It was identified by LabCorp and InSiGHT as benign in association with Lynch Syndrome. The p.Ser260Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Ser260 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. 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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0030
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1805319; hg19: chr7-6036980; COSMIC: COSV56223185; COSMIC: COSV56223185;