7-6004042-G-C

Variant names:

• chr7-6004042-G-C
• rs200313585
• NM_000535.7:c.180C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000535.7(PMS2):​c.180C>G​(p.Asp60Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,586,516 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D60G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (2 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Likely benign reviewed by expert panel B:22
• Conservation: PhyloP100: -0.140
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Y_RNA (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 42 uncertain in NM_000535.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.013067961).
• BP6: Variant 7-6004042-G-C is Benign according to our data. Variant chr7-6004042-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 91315.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000855 (130/151978) while in subpopulation NFE AF = 0.000794 (54/68026). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.180C>G	p.Asp60Glu	missense_variant	Exon 3 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.180C>G	p.Asp60Glu	missense_variant	Exon 3 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 130 AN: 151978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00615

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000915 AC: 229 AN: 250142 AF XY: 0.000879

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00628

Gnomad NFE exome AF: 0.000716

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000717 AC: 1029 AN: 1434538 Hom.: 2 Cov.: 26 AF XY: 0.000664 AC XY: 475 AN XY: 715236

African (AFR) AF: 0.000152 AC: 5 AN: 32872

American (AMR) AF: 0.0000672 AC: 3 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 85370

European-Finnish (FIN) AF: 0.00616 AC: 329 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.000602 AC: 656 AN: 1089282

Other (OTH) AF: 0.000607 AC: 36 AN: 59326

GnomAD4 genome AF: 0.000855 AC: 130 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.00108 AC XY: 80 AN XY: 74226

African (AFR) AF: 0.0000968 AC: 4 AN: 41342

American (AMR) AF: 0.000197 AC: 3 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00615 AC: 65 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68026

Other (OTH) AF: 0.00191 AC: 4 AN: 2092

Alfa AF: 0.000731 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00101 AC: 123

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:22

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.180C>G (p.Asp60Glu) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00095 in 281538 control chromosomes, predominantly at a frequency of 0.00075 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, this data must be interpreted with caution as there is high homology to a pseudogene, which may artificially inflate the allele frequency. c.180C>G has been reported in the literature in individuals affected with Lynch Syndrome or prostate cancer (Grant_2015, van der Klift_2016, Mateo_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Functional studies showed that this variant was not associated with aberrant splicing (van der Klift_2015) and MMR efficiency at 70% of the wild-type levels (Drost_2013). Multiple ClinVar submissions (evaluation after 2014) cite the variant as benign and likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Aug 24, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Asp60Glu variant was identified in 2 of 792 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (van der Klift 2016). The variant was also identified in the following databases: dbSNP (ID: rs200313585) as "With Likely benign allele", ClinVar (4x likely benign, including review by expert panel InSiGHT, 1x benign), Clinvitae, and Insight Hereditary Tumors Database (6x, likely not pathogenic/little clinical significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 271 of 276504 chromosomes (2 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 4 of 24012 chromosomes (freq: 0.0002), Other in 13 of 6456 chromosomes (freq: 0.002), Latino in 2 of 34384 chromosomes (freq: 0.00006), European in 95 of 126292 chromosomes (freq: 0.0008), and Finnish in 157 of 25784 chromosomes (freq: 0.006). The variant was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. A functional study utilizing a cell-free assay found c.180C>G in vitro mismatch repair activity conserved (Drost 2013). Another study investing the splicing pattern of c.180C>G through use of a minigene assay found no aberrant splicing (van der Klift 2015). The p.Asp60 residue is not conserved in mammals and four 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

not provided Benign:6

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26247049, 24027009, 26336887, 27435373) -

Mar 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: BP1, BS3:Supporting -

Hereditary cancer-predisposing syndrome Benign:4

Sep 06, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Oct 28, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 17, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_001322014.2(PMS2):c.180C>G (p.Asp60Glu) has been reported to ClinVar as Likely benign with a status of (3 stars) reviewed by expert panel (Variation ID 91315 as of 2025-01-02). There is a small physicochemical difference between aspartic acid and glutamic acid, which is not likely to impact secondary protein structure as these residues share similar properties. The p.Asp60Glu variant is not predicted to disrupt the existing acceptor splice site The p.Asp60Glu missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The glutamic acid residue at codon 60 of PMS2 is present in Domestic goat and 4 other mammalian species. The nucleotide c.180 in PMS2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign. -

Lynch syndrome 4 Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 24, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

May 27, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	-0.12	N;N
PhyloP100		-0.14
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.63	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.022	B;D
Vest4		0.37
MutPred		0.30		Loss of ubiquitination at K57 (P = 0.0997);Loss of ubiquitination at K57 (P = 0.0997);
MVP		0.91
MPC		0.042
ClinPred		0.0074	T
GERP RS		1.3
PromoterAI		-0.015	Neutral
Varity_R		0.11
gMVP		0.27
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs200313585; hg19: chr7-6043673; COSMIC: COSV104554328;