7-5982995-C-T

Position:

• chr7-5982995-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000265849.12(PMS2):​c.2007-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,449,408 control chromosomes in the GnomAD database, including 14,424 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1460 hom., cov: 30)
  • Exomes 𝑓: 0.14 (12964 hom.)
• Consequence: PMS2 ENST00000265849.12 splice_region, intron
• Scores: Splicing: ADA: 0.00005852
• Clinical Significance: Benign reviewed by expert panel B:21
• Conservation: PhyloP100: -0.223

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 7-5982995-C-T is Benign according to our data. Variant chr7-5982995-C-T is described in ClinVar as [Benign]. Clinvar id is 91327.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5982995-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2007-4G>A		splice_region_variant, intron_variant		ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2007-4G>A		splice_region_variant, intron_variant		1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19434 AN: 150994 Hom.: 1457 Cov.: 30

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.161 AC: 24903 AN: 154878 Hom.: 2020 AF XY: 0.160 AC XY: 13385 AN XY: 83458

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.286

Gnomad SAS exome AF: 0.166

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.144 AC: 186768 AN: 1298298 Hom.: 12964 Cov.: 19 AF XY: 0.146 AC XY: 94526 AN XY: 646644

Gnomad4 AFR exome AF: 0.0330

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.304

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.129 AC: 19440 AN: 151110 Hom.: 1460 Cov.: 30 AF XY: 0.131 AC XY: 9658 AN XY: 73804

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.143

Alfa AF: 0.128 Hom.: 536

Bravo AF: 0.132

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

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	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2017	c.2007-4G>A in intron 11 of PMS2: This variant is not expected to have clinical significance because it has been identified in 29% (3575/12334) of East Asian ch romosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitu te.org; dbSNP rs1805326). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Lynch syndrome 4 Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Jun 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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. -

Lynch syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

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

-

PMS2, INTRON 11, c.2007-4G>A, p.?, (Alias:IVS11-4G>A ), Benign (ACMG 5) The PMS2 c.2007-4G>A variant was identified in 51 of 306 proband chromosomes (frequency: 0.167) from individuals or families with Hereditary Non-Polyposis Colon Cancer (16472587_Hendriks_2006, 16619239_clendenning_2006); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs140788589) “With benign allele”, with a minor allele frequency of 0.1627 (1000 Genomes Project), “InSiGHT Colon Cancer Database”, and the ClinVar database. The variant was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The c.2007-4G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) 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
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.6
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000059
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs1805326; hg19: chr7-6022626; COSMIC: COSV56219344;