chr7-5986899-C-T

Position:

• chr7-5986899-C-T

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.1866G>A​(p.Met622Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,076 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 32)
  • Exomes 𝑓: 0.019 (375 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:26 O:1
• Conservation: PhyloP100: 2.52

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 (MetaRNN=0.0026652813).
• BP6: Variant 7-5986899-C-T is Benign according to our data. Variant chr7-5986899-C-T is described in ClinVar as [Benign]. Clinvar id is 41708.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5986899-C-T is described in Lovd as [Benign]. Variant chr7-5986899-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0158 (2409/152236) while in subpopulation NFE AF= 0.0226 (1535/68006). AF 95% confidence interval is 0.0216. There are 28 homozygotes in gnomad4. There are 1210 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1866G>A	p.Met622Ile	missense_variant	11/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1866G>A	p.Met622Ile	missense_variant	11/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2409 AN: 152118 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0410

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0226

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0164 AC: 4119 AN: 251440 Hom.: 57 AF XY: 0.0163 AC XY: 2209 AN XY: 135912

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.0396

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0194 AC: 28328 AN: 1461840 Hom.: 375 Cov.: 32 AF XY: 0.0188 AC XY: 13679 AN XY: 727218

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00515

Gnomad4 FIN exome AF: 0.0390

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0158 AC: 2409 AN: 152236 Hom.: 28 Cov.: 32 AF XY: 0.0163 AC XY: 1210 AN XY: 74428

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0410

Gnomad4 NFE AF: 0.0226

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0201 Hom.: 39

Bravo AF: 0.0130

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.0176 AC: 2136

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0177

ClinVar

Significance: Benign

Submissions summary: Benign:26 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 16, 2021	The p.Met622Ile variant in PMS2 is classified as benign because it has been identified in 4.1% (1022/25122) of European chromosomes, including 20 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 05, 2015	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2017	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, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 04, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PMS2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Lynch syndrome Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 18, 2015	- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Ovarian neoplasm Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

PMS2, Exon 11, c.1866G>A, p.Met622Ile, Benign, ACMG 5rnThe c.1866G>A variant was identified 10 times in 1950 proband chromosomes in the literature. This variant was found in tumors that are positive for microsatellite instability, negative for immunohistocompatibility complexes and negative for the BRAF gene (17312306_lagerstedt_robinson_2007). It was also found to be negative for PMS2 staining in two independent research papers (15256438_nakagawa_2004, 16472587_hendriks_2006)) and to be MLH1, MSH2, and MSH6 positive (15256438_nakagawa_2004). Berginc found that this missense change is in a region responsible for the interaction of PMS2 with MLH1 and it reduces binding to MLH1 in functional analysis. It was not found in healthy controls (19526325_berginc_2009). In all the literature it was speculated not to be pathogenic (24689082_Hansen_2014, 22949387_thompson_2013, 19526325_berginc_2009, 17312306_lagerstedt_robinson_2007, 16472587_hendriks_2006, 15256438_nakagawa_2004, 11793469_yuan_2002) rnThe variant was also identified in dbSNP (ID: rs1805324) “With untested allele”, with a minor allele frequency of 0.0082 (1000 Genomes Project), HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, and ClinVar database as a benign/likely benign variant. It was submitted to ClinVar 6 times by single and independent submitters as a benign variant. rnThis variant was identified in the 1000 Genomes Project in 32 of 2178 chromosomes (frequency: 0.0147), Exome Variant Server project in 182 of 8600 European American (frequency: 0.021) and 23 of 4406 African American alleles (frequency: 0.0052), increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin.rnThe p.Met622 residue is not conserved in mammals and five out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein.rnThe c.1866G>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.)rnIn 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
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.089	T;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;.;D;.
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.96	N;N;.;.;.
REVEL	Benign	0.090
Sift	Benign	0.25	T;T;.;.;.
Sift4G	Benign	0.30	T;T;.;.;.
Polyphen		0.0020	B;P;.;.;P
Vest4		0.36
MutPred		0.28		Loss of disorder (P = 0.0751);.;.;.;.;
MPC		0.041
ClinPred		0.018	T
GERP RS		5.8
Varity_R		0.087
gMVP		0.34

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: rs1805324; hg19: chr7-6026530; COSMIC: COSV56221681;