chr7-5978618-A-G

Position:

• chr7-5978618-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000535.7(PMS2):​c.2253T>C​(p.Phe751Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.000371 in 1,603,588 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00092 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (12 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:21
• Conservation: PhyloP100: 4.78

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 7-5978618-A-G is Benign according to our data. Variant chr7-5978618-A-G is described in ClinVar as [Benign]. Clinvar id is 36688.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5978618-A-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2253T>C	p.Phe751Phe	synonymous_variant	13/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2253T>C	p.Phe751Phe	synonymous_variant	13/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.000911 AC: 137 AN: 150382 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000542

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.0258

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000266

Gnomad OTH AF: 0.000483

GnomAD3 exomes AF: 0.000176 AC: 44 AN: 249622 Hom.: 5 AF XY: 0.000126 AC XY: 17 AN XY: 134942

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00281

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000800

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000314 AC: 456 AN: 1453104 Hom.: 12 Cov.: 31 AF XY: 0.000302 AC XY: 218 AN XY: 722880

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0000699

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.0000769

Gnomad4 OTH exome AF: 0.000901

GnomAD4 genome AF: 0.000924 AC: 139 AN: 150484 Hom.: 5 Cov.: 32 AF XY: 0.000830 AC XY: 61 AN XY: 73478

Gnomad4 AFR AF: 0.000590

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.0258

Gnomad4 EAS AF: 0.000390

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000288

Gnomad4 NFE AF: 0.000266

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00113 Hom.: 2

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:21

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 29, 2021	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 10, 2016	- -

Lynch syndrome 4 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PMS2: BP4, BP7 -

Hereditary cancer-predisposing syndrome Benign:3

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	Jul 26, 2021	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 13, 2020	- -

Lynch syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

Lynch syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

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, EXON13, c.2253T>C, p.Phe751Phe, Benign (ACMG 5) The PMS2 c.2007-7C>T variant was identified in 16 of 1346 proband chromosomes (frequency: 0.012) from individuals or families with Lynch Syndrome and HNPCC (14756672_Thompson_2004, 20698049_sheng_2010). 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: rs1805325) “With benign allele”, and in the “InSiGHT Colon Cancer Database”. The p.Phe751Phe variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. 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	-0.46
CADD	Benign	9.3
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1805325; hg19: chr7-6018249;