chr7-5986899-C-T

Variant names:

• chr7-5986899-C-T
• rs1805324
• NM_000535.7:c.1866G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000535.7(PMS2):​c.1866G>A​(p.Met622Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,076 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M622V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 32)
  • Exomes 𝑓: 0.019 (375 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:29 O:1
• Conservation: PhyloP100: 2.52
• Publications: 37 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=0.0026652813).
• BP6: Variant 7-5986899-C-T is Benign according to our data. Variant chr7-5986899-C-T is described in ClinVar as Benign. ClinVar VariationId is 41708.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0158 (2409/152236) while in subpopulation NFE AF = 0.0226 (1535/68006). AF 95% confidence interval is 0.0216. There are 28 homozygotes in GnomAd4. There are 1210 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1866G>A	p.Met622Ile	missense_variant	Exon 11 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1866G>A	p.Met622Ile	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2409 AN: 152118 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0410

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0226

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0164 AC: 4119 AN: 251440 AF XY: 0.0163

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0396

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0194 AC: 28328 AN: 1461840 Hom.: 375 Cov.: 32 AF XY: 0.0188 AC XY: 13679 AN XY: 727218

African (AFR) AF: 0.00311 AC: 104 AN: 33480

American (AMR) AF: 0.00525 AC: 235 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 376 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00515 AC: 444 AN: 86250

European-Finnish (FIN) AF: 0.0390 AC: 2083 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0217 AC: 24116 AN: 1111968

Other (OTH) AF: 0.0160 AC: 964 AN: 60394

GnomAD4 genome AF: 0.0158 AC: 2409 AN: 152236 Hom.: 28 Cov.: 32 AF XY: 0.0163 AC XY: 1210 AN XY: 74428

African (AFR) AF: 0.00313 AC: 130 AN: 41560

American (AMR) AF: 0.0119 AC: 181 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4822

European-Finnish (FIN) AF: 0.0410 AC: 434 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0226 AC: 1535 AN: 68006

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.0202 Hom.: 110

Bravo AF: 0.0130

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.0176 AC: 2136

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0177

ClinVar

Significance: Benign

Submissions summary: Benign:29 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Oct 14, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met622Ile variant in PMS2 is classified as benign because it has been identified in 4.1% (1022/25122) of European chromosomes, including 20 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

-

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:7

Oct 05, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sep 21, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 31, 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. -

Hereditary cancer-predisposing syndrome Benign:5

Dec 01, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 05, 2025

Spanish MMR Variant Interpretation Working Group

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 variant c.1866G>A replaces methionine with isoleucine at codon 622 of the PMS2 protein, p.(Met622Ile). The methionine residue is weakly conserved, and there is a small physicochemical difference between methionine and isoleucine. It has a Maximum Credible Allele Frequency (MCAF) above 0.28% in the gnomAD v4.1.0 database (BA1; the allele frequency data may be inaccurate due to possible PMS2CL pseudogene interference). It is a missense variant with a MAPP+PolyPhen-2 prior probability of pathogenicity of <0.11, and SpliceAI, SSF, MaxEnt, NNSPLICE, and GeneSplicer algorithms suggest no impact on splicing (BP4). There are no other PAT/LPAT variants at the same residue. It shows MMR proficiency in in vitro assays and CIMRA functional odds for pathogenicity is 0.03 (Drost 24027009; Rayner 2022 PMID 35451539) (BS3). It has been reported in our Spanish cohort in a patient affected with CRC showing PMS2 loss of expression, but it is also described in patients with tumors showing diverse IHC MMR pattern (PMID: 23017166, 25871621, 19526325, 19132747, 17312306, 15256438 and 24027009). Based on the available evidence, this variant is classified as Benign (Class 1). -

Jan 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 08, 2017

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. -

not provided Benign:3

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: BP4, BS1, BS2 -

Sep 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

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% -

Jun 18, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Ovarian neoplasm Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

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 11, c.1866G>A, p.Met622Ile, Benign, ACMG 5rnThe c.1866G>A variant was identified 10 times in 1950 proband chromosomes in the literature. This variant was found in tumors that are positive for microsatellite instability, negative for immunohistocompatibility complexes and negative for the BRAF gene (17312306_lagerstedt_robinson_2007). It was also found to be negative for PMS2 staining in two independent research papers (15256438_nakagawa_2004, 16472587_hendriks_2006)) and to be MLH1, MSH2, and MSH6 positive (15256438_nakagawa_2004). Berginc found that this missense change is in a region responsible for the interaction of PMS2 with MLH1 and it reduces binding to MLH1 in functional analysis. It was not found in healthy controls (19526325_berginc_2009). In all the literature it was speculated not to be pathogenic (24689082_Hansen_2014, 22949387_thompson_2013, 19526325_berginc_2009, 17312306_lagerstedt_robinson_2007, 16472587_hendriks_2006, 15256438_nakagawa_2004, 11793469_yuan_2002) rnThe variant was also identified in dbSNP (ID: rs1805324) “With untested allele”, with a minor allele frequency of 0.0082 (1000 Genomes Project), HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, and ClinVar database as a benign/likely benign variant. It was submitted to ClinVar 6 times by single and independent submitters as a benign variant. rnThis variant was identified in the 1000 Genomes Project in 32 of 2178 chromosomes (frequency: 0.0147), Exome Variant Server project in 182 of 8600 European American (frequency: 0.021) and 23 of 4406 African American alleles (frequency: 0.0052), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin.rnThe p.Met622 residue is not conserved in mammals and five 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. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein.rnThe c.1866G>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.)rnIn 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.089	T;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;.;D;.
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.
PhyloP100		2.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.96	N;N;.;.;.
REVEL	Benign	0.090
Sift	Benign	0.25	T;T;.;.;.
Sift4G	Benign	0.30	T;T;.;.;.
Polyphen		0.0020	B;P;.;.;P
Vest4		0.36
MutPred		0.28		Loss of disorder (P = 0.0751);.;.;.;.;
MPC		0.041
ClinPred		0.018	T
GERP RS		5.8
Varity_R		0.087
gMVP		0.34
Mutation Taster		=88/12	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: rs1805324; hg19: chr7-6026530; COSMIC: COSV56221681;