rs1805318

chr7-5986976-T-Achr7-5986976-T-Cchr7-5986976-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000535.7(PMS2):c.1789A>T(p.Thr597Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,614,142 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T597A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0089 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (197 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:27 O:1
• Conservation: PhyloP100: -0.538

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039007366).
• BP6: Variant 7-5986976-T-A is Benign according to our data. Variant chr7-5986976-T-A is described in ClinVar as [Benign]. Clinvar id is 41707.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5986976-T-A is described in Lovd as [Benign]. Variant chr7-5986976-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00891 (1357/152322) while in subpopulation NFE AF= 0.0159 (1083/68032). AF 95% confidence interval is 0.0151. There are 10 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1789A>T	p.Thr597Ser	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1789A>T	p.Thr597Ser	missense_variant	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1354 AN: 152204 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00828 AC: 2083 AN: 251444 Hom.: 13 AF XY: 0.00845 AC XY: 1148 AN XY: 135906

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00487

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.0145 AC: 21181 AN: 1461820 Hom.: 197 Cov.: 32 AF XY: 0.0142 AC XY: 10337 AN XY: 727214

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00515

Gnomad4 FIN exome AF: 0.00337

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.00891 AC: 1357 AN: 152322 Hom.: 10 Cov.: 32 AF XY: 0.00832 AC XY: 620 AN XY: 74476

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00426

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0120 Hom.: 8

Bravo AF: 0.00858

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0153 AC: 132

ExAC AF: 0.00821 AC: 997

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:27 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	GeneDx	Nov 11, 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. -
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	-	- -

Lynch syndrome 4 Benign:6

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	Mar 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 24, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jun 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -
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, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PMS2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Lynch syndrome 1 Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Oct 10, 2014	MAF >1% -
Likely benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS2 p.Thr597Ser variant was identified in 27 of 746 proband chromosomes (frequency: 0.036) from Dutch, American, British and French individuals or families with HNPCC, early-onset CRC, MAP or breast cancer and was identified in 37 of 1922 chromosomes (frequency: 0.02) from healthy individuals (Hendriks 2006, Balogh 2006, Lefevre 2012). The variant was also identified in dbSNP (ID: rs1805318) as "With Likely benign allele", ClinVar (classified 10x as benign: InSiGHT, Invitae, GeneDx, Ambry Genetics, Emory Genetics Laboratory, Vantari Genetics, PreventionGenetics, Counsyl, Color Genomics, Biesecker Lab/NIH; 1x likely benign: Pathway Genomics; 1x not provided: ITMI), Clinvitae (7x), MutDB (UniProt Category: Polymorphism), Insight Colon Cancer Gene Variant Database (12x not pathogenic), and the Mismatch Repair Genes Variant Database (3x). The variant was not identified in GeneInsight-COGR, COSMIC, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 2380 of 277222 chromosomes (15 homozygous) at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 1893 of 126716 chromosomes (freq: 0.015) Functional data suggest conflicting effects for this variant. An in vitro pull-down assay demonstrating that this SNP results in defective protein-protein interaction with MLH1, despite the fact that the alteration is outside the putative MLH1 interaction domain, suggests an increased risk factor for tumourigenesis in HNPCC. However, a cell-free MMR functional assay of VUS in PMS2 using MLH1/PMS2 heterodimer to restore a plasmid restriction enzyme site demonstrated 70% activity and was not considered MMR-deficient relative to known pathogenic controls. The p.Thr597Ser 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Lynch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.13
Dann	Benign	0.45
DEOGEN2	Benign	0.068	T;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.36	T;T;.;T;.
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.45	N;N;.;.;.
REVEL	Benign	0.056
Sift	Benign	0.78	T;T;.;.;.
Sift4G	Benign	0.71	T;T;.;.;.
Polyphen		0.0040	B;B;.;.;B
Vest4		0.16
MutPred		0.19		Gain of disorder (P = 0.0411);.;.;.;.;
MVP		0.31
MPC		0.034
ClinPred		0.0048	T
GERP RS		-11
Varity_R		0.030
gMVP		0.16

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: rs1805318; hg19: chr7-6026607; COSMIC: COSV104554309;