rs201343342

chr7-6006002-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP3 BP4_Moderate BP6

The NM_000535.7(PMS2):c.53T>C(p.Ile18Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,610,676 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. I18V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:7
• Conservation: PhyloP100: 8.91

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 Likely_benign. Variant got -2 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.12846899).
• BP6: Variant 7-6006002-A-G is Benign according to our data. Variant chr7-6006002-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41714.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=10, Benign=2}. Variant chr7-6006002-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.53T>C	p.Ile18Thr	missense_variant	2/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.53T>C	p.Ile18Thr	missense_variant	2/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000366 AC: 90 AN: 245578 Hom.: 0 AF XY: 0.000418 AC XY: 56 AN XY: 134084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00734

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000164 AC: 239 AN: 1458462 Hom.: 1 Cov.: 31 AF XY: 0.000183 AC XY: 133 AN XY: 725560

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00593

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.000382

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000275 AC: 32

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:4 Benign:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 14, 2023	Variant summary: PMS2 c.53T>C (p.Ile18Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 245578 control chromosomes. The observed variant frequency is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is benign. However, the variant is located in a PMS2 region that shows high homology to pseudogenes, therefore this frequency data should be taken with caution. c.53T>C has been observed in a Lynch Syndrome patient with no other pathogenic mutations and with tumors that exhibited isolated loss of PMS2 expression by IHC (Vaughn_2010). It was also reported in patients with endometrial, kidney, breast and colorectal cancer, without strong evidence for causality (example, Lu_2015, Tung_2015, Tung_2016, Yurgelun_2017, Krivokuca_2021, Guindalini_2022). This variant has also been reported in an unaffected sibling and a proband in compound heterozygosity with a pathogenic exon 5 to 12 deletion (Shuen_2019). Both siblings demonstrated absent staining of PMS2 on non-neoplastic tissue. In addition, a recent large scale case-control study of breast cancer reported this variant in 13/53461 controls and 8/60466 cases (Dorling_2021). At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.2808_2811del, p.Ala938Profs*21; Tung_2016), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Shuen_2019). The most pronounced variant effect results in approximately 21% mismatch repair (MMR) activity. The authors suggested that an MMR activity of 10% to 20% may represent an intermediate phenotype between classic CMMRD and Lynch syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 27060170, 35264596, 22703879, 34284872, 26689913, 30608896, 25186627, 26976419, 20205264, 28135145, 30447919, 33471991). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=8; Likely benign, n=3; Benign, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 20, 2020	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.53T>C, in exon 2 that results in an amino acid change, p.Ile18Thr. This sequence change has been described in the gnomAD database with a low population frequency of 0.03% in the overall population and a relatively high population frequency of 0.72% in the Ashkenazi Jewish population (dbSNP rs201343342). This sequence change was identified in a patient with colorectal cancer whose tumor exhibited isolated loss of PMS2 expression by IHC (Vaughn et al., 2010). The p.Ile18Thr change was identified in an Ashkenazi Jewish breast cancer patient who was also found to have a pathogenic sequence change in BRCA2 (Tung et al., 2016). The p.Ile18Thr change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Ile18Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile18Thr change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2017	This variant is denoted PMS2 c.53T>C at the cDNA level, p.Ile18Thr (I18T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant was observed in at least one individual undergoing genetic testing for Lynch syndrome with a tumor that exhibited isolated loss of PMS2 by immunohistochemistry (Vaughn 2010). This variant was also reported in a patient with endometrial cancer, another with renal cancer, one with breast cancer who also carried a pathogenic variant in BRCA2 and in 2/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012, Lu 2015, Tung 2016). PMS2 Ile18Thr was not observed in approximately 3,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ile18Thr occurs at a position that is conserved across species and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Ile18Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 20, 2019	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 25, 2021	- -

Lynch syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 30, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Lynch syndrome 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 01, 2018	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS2 p.Ile18Thr variant was identified in 6 of 2462 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer, hemophilia A, and atherosclerosis (Gorski 2016, Tung 20016, Vaughn 2010, Johnston 2012). The variant was also identified in dbSNP (ID: rs201343342 as “with uncertain significance allele”), and ClinVar (6x as uncertain significance by GeneDx, Children's Hospital of Philadelphia, Color Genomics, Quest Diagnostics, Fulgent Genetics and NIH; 1x as likely benign by Ambry Genetics; and 1x as benign by Invitae) and the Insight Hereditary Tumors Database (1x as effect unknown). The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang Colon Cancer, or the Mismatch Repair Genes Variant database. The variant was identified in control databases in 88 of 271252 chromosomes at a frequency of 0.0003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Other in 1 of 6380 chromosomes (freq: 0.0002), European Non-Finnish in 13 of 122684 chromosomes (freq: 0.0001), and Ashkenazi Jewish in 74 of 9990 chromosomes (freq: 0.007); it was not observed in the African, Latino, East Asian, European Finnish, or South Asian populations. The p.Ile18Thr residue is conserved across mammals and other organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in this laboratory with a co-occurring, pathogenic MSH6 variant (c.3840_3846del, p.Glu1281Leufs*44), increasing the likelihood that the p.Ile18Thr 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. -

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

Mar 30, 2023

- -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

PMS2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.65		Loss of stability (P = 0.039);Loss of stability (P = 0.039);
MVP		0.98
MPC		0.29
ClinPred		0.37	T
GERP RS		5.7
Varity_R		0.75
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201343342; hg19: chr7-6045633;