rs63751132

Positions:

chr7-5987198-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The ENST00000265849.12(PMS2):c.1567T>A(p.Ser523Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S523C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PMS2
ENST00000265849.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:9O:1

Conservation

PhyloP100: 0.506

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.072170705).

BP6

Variant 7-5987198-A-T is Benign according to our data. Variant chr7-5987198-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127763.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=8, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.1567T>A	p.Ser523Thr	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 linkuse as main transcript	c.1567T>A	p.Ser523Thr	missense_variant	11/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251178

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000163

AC:

238

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000156

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000210

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 28, 2018	This alteration is classified as likely 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

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PMS2: BP1, BP4, BP5 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28135145, 22290698, 15470502, 24728327, 27930734, 32095738, 31992580, 17016615, 26845104, 26976419, 20186688, 26689913, 26232782, 31159747, 31433215, 31391288, 32547938, 28166811, 12900794, 22949379, 34284872, 35449176, 33471991, 30374176, 37937776, 38773787) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 07, 2022	- -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: PMS2 c.1567T>A (p.Ser523Thr) results in a conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251178 control chromosomes, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), however this data must be interpreted with caution as the sequencing techology utalized does not distinguish between PMS2 and highly homologous pseudogenes. c.1567T>A has been reported in the literature in individuals affected with Lynch Syndrome and other types of cancer (Nomura_2015, He_2016, Shirts_2016, Tung_2016, Yurgelun_2017, Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (PMS2 c.1492del11; Nomura_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 26689913, 26845104, 26976419, 27930734, 28135145, 26232782). Fourteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=7) and likely benign (n=7) Based on the evidence outlined above, the variant was classified as likely benign. -

Lynch syndrome 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 29, 2017	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 18, 2021

- -

PMS2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2024

The PMS2 c.1567T>A variant is predicted to result in the amino acid substitution p.Ser523Thr. This variant has been reported in individuals with breast cancer and colon cancer (Table 4, Balogh et al. 2006. PubMed ID: 17016615; Table S1, Shirts et al. 2016. PubMed ID: 26845104; Table A2, Tung et al. 2016. PubMed ID: 26976419; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table S5, Tsaousis et al. 2019. PubMed ID: 31159747; Table 1, Okkels et al. 2019. PubMed ID: 31433215; Table 1, Wang et al. 2020. PubMed ID: 31992580). In silico tools predict this variant to be tolerated (Table 3, Ali et al. 2012. PubMed ID: 22290698). This variant is reported in 0.045% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127763/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Carcinoma of colon

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PMS2 p.Ser523Thr variant was identified in 2 of 3900 proband chromosomes (frequency: 0.0005) from individuals or families with breast or colon cancer (Shirts 2015, Tung 2016). The variant was also identified in dbSNP (ID: rs63751132 as "With Uncertain significance allele"), ClinVar (2x as likely benign by Ambry Genetics and Invitae and 4x as uncertain significance by Counsyl, GeneDx, and two other clinical laboratories), Mismatch Repair Genes Variant Database, and InSiGHT Hereditary Tumors database. The variant was not identified in the COGR, Cosmic, MutDB, or Zhejiang University database. The variant was identified in control databases in 46 of 276928 chromosomes at a frequency of 0.0002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 28 of 126528 chromosomes (freq: 0.0002), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34418 chromosomes (freq: 0.00003), Finnish in 2 of 25786 chromosomes (freq: 0.00008), and South Asian in 14 of 30782 chromosomes (freq: 0.0005); it was not observed in the African, Ashkenazi Jewish, or East Asian populations. The variant was identified by our lab in an individual with an MLH1/PMS2 deficient rectal tumour with a co-occurring pathogenic MLH1 variant (c.1790G>A, p.Trp597*), increasing the likelihood that the p.Ser523Thr variant does not have clinical significance. The variant was identified with a co-occurring pathogenic PMS2 (PMS2 c.1492del11; Nomura 2015), also increasing the likelihood that the p.Ser523Thr variant does not have clinical significance. The p.Ser523 residue is not conserved in mammals and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Hereditary nonpolyposis colon cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Jan 31, 2019

This variant is found in population databases at a higher frequency than expected for pathogenic variants in the PMS2 gene (exac.broadinstitute.org, Kobayashi 2017). This variant is not located in a functional domain and its genomic position is not highly conserved. Computational algorithms classify this variant as tolerated. This variant has an entry in the ClinVar database (Variation ID: 127763) and has been classified as likely benign by another laboratory where it has been seen in patients with other genetic causes that explain their cancer history. Familial cosegregation analysis showed a likelihood ratio of 0.85 (Thompson 2003), adding more evidence that the variant is benign. Bayesian analysis integrating all this data gives a 2% probability of pathogenicity (Tavtigian 2018, Tsai 2018), which is consistent with a classification of likely benign. Therefore, PMS2 p.S523T is now classified as likely benign. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.41

CADD

Benign

2.6

DANN

Benign

0.82

DEOGEN2

Benign

0.11

T;.;.;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.29

T;T;.;T;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.072

T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.9

L;.;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.97

N;N;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.44

T;T;.;.;.

Sift4G

Benign

0.38

T;T;.;.;.

Polyphen

0.55

P;P;.;.;P

Vest4

0.15

MVP

0.44

MPC

0.035

ClinPred

0.033

GERP RS

2.3

Varity_R

0.021

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over