7-6006003-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000535.7(PMS2):c.52A>G(p.Ile18Val) variant causes a missense change. The variant allele was found at a frequency of 0.011 in 1,610,660 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I18T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0083 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (123 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:32 O:2
• Conservation: PhyloP100: 5.91

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009115964).
• BP6: Variant 7-6006003-T-C is Benign according to our data. Variant chr7-6006003-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 41713.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-6006003-T-C is described in Lovd as [Benign]. Variant chr7-6006003-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0112 (16400/1458362) while in subpopulation NFE AF= 0.0122 (13562/1111660). AF 95% confidence interval is 0.012. There are 123 homozygotes in gnomad4_exome. There are 8035 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.52A>G	p.Ile18Val	missense_variant	2/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.52A>G	p.Ile18Val	missense_variant	2/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1265 AN: 152180 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00901 AC: 2213 AN: 245572 Hom.: 21 AF XY: 0.00917 AC XY: 1229 AN XY: 134082

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00306

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00924

GnomAD4 exome AF: 0.0112 AC: 16400 AN: 1458362 Hom.: 123 Cov.: 31 AF XY: 0.0111 AC XY: 8035 AN XY: 725510

Gnomad4 AFR exome AF: 0.00174

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00370

Gnomad4 FIN exome AF: 0.0324

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.00832 AC: 1267 AN: 152298 Hom.: 9 Cov.: 32 AF XY: 0.00834 AC XY: 621 AN XY: 74462

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00439

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00582 Hom.: 2

Bravo AF: 0.00652

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00331 AC: 9

ESP6500EA AF: 0.0113 AC: 52

ExAC AF: 0.00899 AC: 1048

EpiCase AF: 0.0104

EpiControl AF: 0.0105

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:32 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 19, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2016	- -
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	- -

Hereditary cancer-predisposing syndrome Benign:7

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 03, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 26, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2020	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not provided Benign:6 Other:1

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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PMS2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2017	Variant summary: The PMS2 c.52A>G (p.Ile18Val) variant located in the Histidine kinase-like ATPase, C-terminal domain of the protein (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, a functional study indicates the variant does not affect MMR activity (Drost_2013. This variant was found in 2457/271244 control chromosomes (gnomAD) including 22 homozygotes at a frequency of 0.0090519, which is approximately 80 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. However, this observation needs to be cautiously considered because the sequencing technology (exome and genome sequencing) used cannot rule out the fact that the pseudogene could have been amplified. Several publications have cited the variant in affected individuals with Lynch Syndrome or related disorders, including reports of lack of cosegregation with disease in multiple families (Leongamornlert_2014 and Hendriks_2006). This variant also co-occurred with another pathogenic variant in a CRC patient and a suspected LS patient (Haraldsdottir_2017 and van der Klift_2016). In addition, in multiple internal LCA samples this variant was found to co-occur with another pathogenic or likely pathogenic variants such as PMS2 c.137G>T (p.Ser46Ile), MSH6 c.1634_1637delAAGA (p.Lys545fsX25), BRCA2 c.4647_4650delAGAG (p.Lys1549fsX18) MUTYH c.933+3A>C, MSH2 c.2038C>T (p.Arg680X) and PMS2 c.251-2A>T and MLH1 c.955G>T (p.Glu319X). Furthermore, multiple clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as likely benign/benign. Therefore due to the lack of cosegregation with disease, multiple co-occurrences with a pathogenic/likely pathogenic variant, and multiple clinical diagnostic laboratories classifying the variant as "likely benign/benign," the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Lynch syndrome 4 Benign:6

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Feb 05, 2016	- -

Lynch syndrome 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Oct 17, 2014	- -
Likely benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Oct 10, 2014	MAF >1% in a specific ethnic group (European American) -

Mismatch repair cancer syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jun 03, 2019

- -

Lynch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Dec 22, 2015

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

PMS2, EXON2, c.52A>G, p.Ile18Val, Heterozygous, Benign The PMS2 p.Ile18Val variant was identified in 11 of 1400 proband chromosomes (frequency: 0.008) from individuals or families with colorectal cancer, prostate cancer, or common variable immunodeficiency disorder and was present in 1 of 1552 control chromosomes (frequency: 0.0006) from healthy individuals (Clendenning 2006, Hendriks 2006, Van Schouwenburg 2015, van der Klift 2016, Leongamornlert 2014, Bodian 2014). The variant was also identified in dbSNP (ID: rs63750123) as "With other allele", and ClinVar (classified as benign by fifteen submitters; as likely benign by six submitters). The variant was identified in control databases in 2457 of 271244 chromosomes (22 homozygous) at a frequency of 0.009, 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: African in 44 of 22858 chromosomes (freq: 0.002), Other in 50 of 6380 chromosomes (freq: 0.008), Latino in 65 of 34296 chromosomes (freq: 0.002), European in 1387 of 122680 chromosomes (freq: 0.01), Ashkenazi Jewish in 5 of 9990 chromosomes (freq: 0.0005), Finnish in 811 of 25762 chromosomes (freq: 0.03), and South Asian in 95 of 30546 chromosomes (freq: 0.003); it was not observed in the East Asian population. The p.Ile18 residue is conserved across mammals and other organisms, and four out of five 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, the variant demonstrated repair efficiency similar to wild type and repair-proficient controls (Drost 2013). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. Assessment Date: 2019/07/22 References (PMIDs): 16619239, 24027009, 16472587, 26122175, 27435373, 24556621, 24728327 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.89	N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.66
MVP		0.93
MPC		0.25
ClinPred		0.019	T
GERP RS		5.7
Varity_R		0.38
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs63750123; hg19: chr7-6045634; COSMIC: COSV56149828; COSMIC: COSV56149828;