rs55954143

chr7-5982998-G-Achr7-5982998-G-Cchr7-5982998-G-T

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.2007-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,409,502 control chromosomes in the GnomAD database, including 4,466 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 0.12 (1391 hom., cov: 31)
  • Exomes 𝑓: 0.068 (3075 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002982
• Clinical Significance: Benign reviewed by expert panel B:19
• Conservation: PhyloP100: 0.672

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=-0.75).
• BP6: Variant 7-5982998-G-A is Benign according to our data. Variant chr7-5982998-G-A is described in ClinVar as [Benign]. Clinvar id is 36687.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5982998-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2007-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2007-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17653 AN: 150504 Hom.: 1379 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.0876

Gnomad SAS AF: 0.0897

Gnomad FIN AF: 0.0908

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0951

GnomAD3 exomes AF: 0.0758 AC: 11269 AN: 148764 Hom.: 514 AF XY: 0.0743 AC XY: 5950 AN XY: 80070

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.0885

Gnomad SAS exome AF: 0.0827

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0662

Gnomad OTH exome AF: 0.0621

GnomAD4 exome AF: 0.0684 AC: 86153 AN: 1258874 Hom.: 3075 Cov.: 18 AF XY: 0.0688 AC XY: 43227 AN XY: 628484

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.0356

Gnomad4 ASJ exome AF: 0.0395

Gnomad4 EAS exome AF: 0.0828

Gnomad4 SAS exome AF: 0.0845

Gnomad4 FIN exome AF: 0.0928

Gnomad4 NFE exome AF: 0.0620

Gnomad4 OTH exome AF: 0.0761

GnomAD4 genome AF: 0.117 AC: 17693 AN: 150628 Hom.: 1391 Cov.: 31 AF XY: 0.118 AC XY: 8655 AN XY: 73644

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.0596

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.0877

Gnomad4 SAS AF: 0.0890

Gnomad4 FIN AF: 0.0908

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.0941

Alfa AF: 0.0808 Hom.: 207

Bravo AF: 0.123

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2018	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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:5

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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
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 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 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	- -

Lynch syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 27, 2013	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 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

-

The PMS2 c.2007-7C>T variant was identified in 24 of 1372 proband chromosomes (frequency: 0.017) from individuals or families with Lynch syndrome, but was classified as a benign polymorphism (Hansen 2014, Hendriks 2006, Niessen 2009, Sheng 2010, van der Klift 2016). The variant was also identified in dbSNP (rs55954143) with benign allele, ClinVar 6x (classified as benign, reviewed by an expert panel), Genesight-COGR, Insight Colon Cancer Gene Variant Database (as benign), and Mismatch Repair Genes Variant Database. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, MMR Gene Unclassified Variants Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 14684 of 174456 chromosomes (776 homozygous) at a frequency of 0.08 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 3950 of 15996 chromosomes (freq: 0.247), East Asian in 1045 of 11848 chromosomes (freq: 0.088), European (Finnish) in 1617 of 19226 chromosomes (freq: 0.084), South Asian in 1722 of 20892 chromosomes (freq: 0.082), Other in 326 of 4640 chromosomes (freq: 0.07), European (Non-Finnish) in 4958 of 72394 chromosomes (freq: 0.068), Ashkenazi Jewish* in 329 of 7828 chromosomes (freq: 0.042). 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	-0.75
Cadd	Benign	7.7
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs55954143; hg19: chr7-6022629;