7-5987234-T-C

Variant names:

• chr7-5987234-T-C
• rs2228007
• NM_000535.7:c.1531A>G

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.1531A>G​(p.Thr511Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,614,066 control chromosomes in the GnomAD database, including 678 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T511M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.021 (53 hom., cov: 32)
  • Exomes 𝑓: 0.027 (625 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:26 O:1
• Conservation: PhyloP100: -0.352
• Publications: 32 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=0.0029952526).
• BP6: Variant 7-5987234-T-C is Benign according to our data. Variant chr7-5987234-T-C is described in ClinVar as Benign. ClinVar VariationId is 41703.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0215 (3267/152240) while in subpopulation NFE AF = 0.0277 (1886/68026). AF 95% confidence interval is 0.0267. There are 53 homozygotes in GnomAd4. There are 1694 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1531A>G	p.Thr511Ala	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.1531A>G	p.Thr511Ala	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3267 AN: 152122 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0246 AC: 6176 AN: 251328 AF XY: 0.0254

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0315

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0272 AC: 39709 AN: 1461826 Hom.: 625 Cov.: 47 AF XY: 0.0270 AC XY: 19627 AN XY: 727210

African (AFR) AF: 0.00490 AC: 164 AN: 33480

American (AMR) AF: 0.0119 AC: 532 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 823 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0208 AC: 1797 AN: 86258

European-Finnish (FIN) AF: 0.0516 AC: 2753 AN: 53388

Middle Eastern (MID) AF: 0.0271 AC: 156 AN: 5766

European-Non Finnish (NFE) AF: 0.0288 AC: 31987 AN: 1111984

Other (OTH) AF: 0.0248 AC: 1497 AN: 60394

GnomAD4 genome AF: 0.0215 AC: 3267 AN: 152240 Hom.: 53 Cov.: 32 AF XY: 0.0228 AC XY: 1694 AN XY: 74434

African (AFR) AF: 0.00631 AC: 262 AN: 41550

American (AMR) AF: 0.0161 AC: 246 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0381 AC: 132 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4826

European-Finnish (FIN) AF: 0.0538 AC: 570 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0277 AC: 1886 AN: 68026

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0246 Hom.: 77

Bravo AF: 0.0181

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0283 AC: 109

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0250 AC: 3041

EpiCase AF: 0.0285

EpiControl AF: 0.0268

ClinVar

Significance: Benign

Submissions summary: Benign:26 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 28, 2014

Eurofins Ntd Llc (ga)

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

- -

Sep 03, 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. -

-

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Lynch syndrome 4 Benign:7

May 11, 2023

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. -

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

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 2017

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:4

Oct 14, 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. -

Dec 21, 2015

Vantari Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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% -

Sep 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

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, EXON11, c.1531A>G, p.Thr511Ala, Benign (ACMG 5) The c.1531A>G variant was identified in 6 of 368 proband chromosomes (frequency: 0.016) from individuals or families with HNPCC and Lynch syndrome; 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 present in individuals that tested immunohistocompatibility PMS2 negative but positive for MLH1, MSH2 and MSH 6. Tumours were also found to be microsatellite instability high. (10479499_Basil_1999, 15256438_Nakagawa, 16619239_Clenndening_2006, 24027009_Drost_2013) The variant was also identified in dbSNP (ID: rs2228007) “With untested allele”, with a minor allele frequency of 0.011 (1000 Genomes Project), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, and ClinVar database as a benign variant.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) with 6 separate submitters. 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 26 of 2178 chromosomes (frequency: 0.0119), Exome Variant Server project in 270 of 13006 European American/African American alleles (frequency: 0.02), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Thr511 residue is not conserved in mammals and the variant amino acid Threonine (Thr) is present in Macaques and Trichoplax adhaerens, 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 but it increases the likelihood that this variant does not have clinical significance. The c.1531A>G 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, the clinical significance of this variant satisfies our laboratory requirements as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.32
DANN	Benign	0.17
DEOGEN2	Benign	0.087	T;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.40	T;T;.;T;.
MetaRNN	Benign	0.0030	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.76	N;.;.;.;.
PhyloP100		-0.35
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.75	N;N;.;.;.
REVEL	Benign	0.031
Sift	Benign	0.76	T;T;.;.;.
Sift4G	Benign	0.88	T;T;.;.;.
Polyphen		0.0	B;B;.;.;B
Vest4		0.017
MPC		0.036
ClinPred		0.0021	T
GERP RS		1.9
Varity_R		0.016
gMVP		0.18
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228007; hg19: chr7-6026865; COSMIC: COSV104554297;