rs1805321

Variant names:

• chr7-5987357-G-A
• rs1805321
• NM_000535.7:c.1408C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.1408C>T​(p.Pro470Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,613,638 control chromosomes in the GnomAD database, including 130,152 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P470L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.37 (10854 hom., cov: 31)
  • Exomes 𝑓: 0.40 (119298 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:27 O:1
• Conservation: PhyloP100: 0.283
• Publications: 96 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=7.440746E-4).
• BP6: Variant 7-5987357-G-A is Benign according to our data. Variant chr7-5987357-G-A is described in ClinVar as Benign. ClinVar VariationId is 36685.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1408C>T	p.Pro470Ser	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.1408C>T	p.Pro470Ser	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56479 AN: 151820 Hom.: 10845 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.384

GnomAD2 exomes AF: 0.388 AC: 97518 AN: 251474 AF XY: 0.391

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.402 AC: 587541 AN: 1461700 Hom.: 119298 Cov.: 49 AF XY: 0.403 AC XY: 292826 AN XY: 727146

African (AFR) AF: 0.280 AC: 9366 AN: 33478

American (AMR) AF: 0.387 AC: 17327 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 11742 AN: 26134

East Asian (EAS) AF: 0.376 AC: 14945 AN: 39696

South Asian (SAS) AF: 0.359 AC: 30977 AN: 86256

European-Finnish (FIN) AF: 0.350 AC: 18671 AN: 53416

Middle Eastern (MID) AF: 0.454 AC: 2617 AN: 5768

European-Non Finnish (NFE) AF: 0.412 AC: 457847 AN: 1111834

Other (OTH) AF: 0.398 AC: 24049 AN: 60394

GnomAD4 genome AF: 0.372 AC: 56519 AN: 151938 Hom.: 10854 Cov.: 31 AF XY: 0.368 AC XY: 27349 AN XY: 74280

African (AFR) AF: 0.287 AC: 11885 AN: 41424

American (AMR) AF: 0.397 AC: 6052 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1535 AN: 3468

East Asian (EAS) AF: 0.383 AC: 1979 AN: 5172

South Asian (SAS) AF: 0.351 AC: 1693 AN: 4820

European-Finnish (FIN) AF: 0.352 AC: 3717 AN: 10562

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.418 AC: 28371 AN: 67938

Other (OTH) AF: 0.382 AC: 806 AN: 2112

Alfa AF: 0.398 Hom.: 12656

Bravo AF: 0.373

TwinsUK AF: 0.415 AC: 1537

ALSPAC AF: 0.402 AC: 1551

ESP6500AA AF: 0.282 AC: 1242

ESP6500EA AF: 0.421 AC: 3620

ExAC AF: 0.385 AC: 46782

Asia WGS AF: 0.329 AC: 1146 AN: 3478

EpiCase AF: 0.423

EpiControl AF: 0.426

ClinVar

Significance: Benign

Submissions summary: Benign:27 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

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

- -

Apr 16, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Apr 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro470Ser in Exon 11 of PMS2: This variant is not expected to have clinical si gnificance because it has been identified in 45% (4560/10152) of Ashkenazi Jewis h chromosomes and 41% (52732/126656) of European chromosomes by the Genome Aggre gation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs1805321). -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 4 Benign:5

Aug 18, 2017

IntelligeneCG

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

- -

Jul 06, 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: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 10, 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. -

Lynch syndrome Benign:3

Jun 22, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Oct 03, 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:3

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24728327) -

Hereditary cancer-predisposing syndrome Benign:3

Nov 05, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 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. -

Mar 06, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mismatch repair cancer syndrome 4 Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1

Jul 24, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

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

The PMS2 p.Pro470Ser variant was identified in 464 of 1592 chromosomes (frequency: 0.294) from individuals with colorectal and/or endometrial cancer, suspected HNPCC and artherosclerosis (Borras_2013_2370975, Clendenning_2006_16619239, Gururangan_2008_17993636, He_2011_21984973, Hendriks_2006_16472587, Johnston_2012_22703879_supplementary, Kim_2004_15448003); however, control chromosomes were not analyzed in all of the studies, thus the prevalence of the variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs1805321) “With benign allele”, MutDB, and InSiGHT Colon Cancer DB. The variant was listed in the NHLBI Exome Sequencing Project in 3620 of 8600 European American alleles (frequency: 0.421) and in 1242 of 4856 African American alleles (frequency:0.256), increasing the likelihood that it may be a polymorphism in certain populations. The p.Pro470Ser variant is not conserved/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. This variant is unlikely to have an effect on splicing as it is downstream of the exon/intron junction. 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
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.6
DANN	Benign	0.29
DEOGEN2	Benign	0.057	T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.48	T;T;.;T;.
MetaRNN	Benign	0.00074	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.;.;.
PhyloP100		0.28
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.20	N;N;.;.;.
REVEL	Benign	0.085
Sift	Benign	0.84	T;T;.;.;.
Sift4G	Benign	0.72	T;T;.;.;.
Polyphen		0.0020	B;B;.;.;B
Vest4		0.036
MPC		0.037
ClinPred		0.00014	T
GERP RS		0.57
Varity_R		0.012
gMVP		0.28
Mutation Taster		=98/2	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: rs1805321; hg19: chr7-6026988; COSMIC: COSV56220401;