chr7-5982995-C-T

Variant names:

• chr7-5982995-C-T
• rs1805326
• NM_000535.7:c.2007-4G>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.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 NM_000535.7 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]

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 rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2007-4G>A		splice_region_variant, intron_variant	Intron 11 of 14	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2007-4G>A		splice_region_variant, intron_variant	Intron 11 of 14	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

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 02, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 4 Benign:6

Jun 13, 2017

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Mar 31, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 24, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Endometrial carcinoma Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;