7-5987054-G-T

Variant names:

• chr7-5987054-G-T
• rs63750055
• NM_000535.7:c.1711C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000535.7(PMS2):​c.1711C>A​(p.Leu571Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,614,158 control chromosomes in the GnomAD database, including 31 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. L571R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0073 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (14 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:25 O:1
• Conservation: PhyloP100: -0.991
• Publications: 22 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 43 uncertain in NM_000535.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045543313).
• BP6: Variant 7-5987054-G-T is Benign according to our data. Variant chr7-5987054-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 41706.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00733 (1116/152280) while in subpopulation AFR AF = 0.0213 (886/41558). AF 95% confidence interval is 0.0202. There are 17 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1711C>A	p.Leu571Ile	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.1711C>A	p.Leu571Ile	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1115 AN: 152162 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00964

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00226 AC: 567 AN: 251366 AF XY: 0.00198

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00118 AC: 1725 AN: 1461878 Hom.: 14 Cov.: 32 AF XY: 0.00108 AC XY: 783 AN XY: 727236

African (AFR) AF: 0.0225 AC: 753 AN: 33480

American (AMR) AF: 0.00351 AC: 157 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.000542 AC: 603 AN: 1112010

Other (OTH) AF: 0.00253 AC: 153 AN: 60394

GnomAD4 genome AF: 0.00733 AC: 1116 AN: 152280 Hom.: 17 Cov.: 32 AF XY: 0.00712 AC XY: 530 AN XY: 74460

African (AFR) AF: 0.0213 AC: 886 AN: 41558

American (AMR) AF: 0.00956 AC: 146 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68034

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00284 Hom.: 6

Bravo AF: 0.00884

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00243 AC: 295

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00148

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:25 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:7

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

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Mar 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 16, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:5 Other:1

Oct 06, 2016

Eurofins Ntd Llc (ga)

Significance: Likely 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

Jan 06, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 07, 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.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 30, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:5

Dec 09, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 18, 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.

Jan 22, 2016

Vantari Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 30, 2017

True Health Diagnostics

Significance: 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.1711C>A replaces leucine with isoleucine at codon 571 of the PMS2 protein (p.Leu571Ile). The leucine residue is weakly conserved, and there is a small physicochemical difference between leucine and isoleucine. The variant c.1711C>A has a Maximum Credible Allele Frequency (MCAF) above 0.28% in gnomAD v4.1.0 database (24 homozygotes) (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 it is not predicted to affect splicing according to MaxEntScan/NNSplice/SpliceAI algorithms (BP4). There are no other described class 4/5 variants located at the same residue. Its functional odds for Pathogenicity are between 0.05 and 0.48 as per CIMRA assay (BS3_supp). It has been reported in our Spanish cohort in a patient affected with CRC showing PMS2 loss of expression and co-occurrence with a PMS2 likely pathogenic variant (phase unknown). Based on the available evidence, this variant is classified as Benign (Class 1).

Lynch syndrome 4 Benign:5

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.

Jul 19, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 16, 2018

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). 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.

Carcinoma of colon Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Leu571Ile variant was identified 5 of 2018 proband chromosomes (frequency: 0.002) from Dutch and American individuals or families with Lynch Syndrome, suspected Lynch Syndrome, or individuals being ascertained for atherosclerosis phenotypes (van der Klift 2016, Johnston 2012, Clendenning 2006). The variant was identified in the following databases: dbSNP (ID: rs63750055) as “other”, ClinVar (classified as likely benign, reviewed by an expert panel; classified as likely benign by InSIGHT, Vantari Genetics, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics; benign by GeneDx, Ambry Genetics, Invitae; uncertain significance by Biesecker Lab/Human Development Section-NIH; and classification not provided by ITMI), Clinvitae (4X), Insight Colon Cancer Gene Variant Database (3X), and Insight Hereditary Tumors Database; but was not identified in COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database and the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 760 (10 homozygous) of 277148 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following population at a frequency greater than 1%: African in 506 (10 homozygous) of 23994 chromosomes (freq: 0.021). The p.Leu571 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. The variant was identified by our laboratory in an individual with a co-occurring pathogenic variant (PMS2, c.2276-?_2445+?del), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% in African population

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.039
DANN	Benign	0.83
DEOGEN2	Benign	0.062	T;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.41	T;T;.;T;.
MetaRNN	Benign	0.0046	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;.;.
PhyloP100		-0.99
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.40	N;N;.;.;.
REVEL	Benign	0.022
Sift	Benign	0.47	T;T;.;.;.
Sift4G	Benign	0.47	T;T;.;.;.
Vest4		0.16
ClinPred		0.00084	T
GERP RS		-3.3
Varity_R		0.023
gMVP		0.10
Mutation Taster		=99/1	polymorphism

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: rs63750055; hg19: chr7-6026685; COSMIC: COSV56221469;