rs1805321

Positions:

• chr7-5987357-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• 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

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=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 id is 36685.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5987357-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1408C>T	p.Pro470Ser	missense_variant	11/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1408C>T	p.Pro470Ser	missense_variant	11/15	1	NM_000535.7	ENSP00000265849	P3

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

GnomAD3 exomes AF: 0.388 AC: 97518 AN: 251474 Hom.: 19196 AF XY: 0.391 AC XY: 53079 AN XY: 135908

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 SAS exome AF: 0.354

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

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.387

Gnomad4 ASJ exome AF: 0.449

Gnomad4 EAS exome AF: 0.376

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.412

Gnomad4 OTH exome AF: 0.398

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

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.397

Gnomad4 ASJ AF: 0.443

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.418

Gnomad4 OTH AF: 0.382

Alfa AF: 0.406 Hom.: 7822

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2017	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). -

Lynch syndrome 4 Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -

Lynch syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327) -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 14, 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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 06, 2021	- -

Mismatch repair cancer syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Lynch syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
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

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: rs1805321; hg19: chr7-6026988; COSMIC: COSV56220401;