Genetic Variant NM_000535.7:c.180C>G (chr7-6004042-G-C) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign reviewed by expert panel B:22

Conservation

PhyloP100: -0.140

Publications

14 publications found

Variant links:

COSMIC-nc: COSV104554328

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

PMS2 links:

Y_RNA (HGNC:):

Y_RNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMS2	NM_000535.7	MANE Select	c.180C>G	p.Asp60Glu	missense	Exon 3 of 15	NP_000526.2
PMS2	NM_001406866.1		c.366C>G	p.Asp122Glu	missense	Exon 4 of 16	NP_001393795.1
PMS2	NM_001322014.2		c.180C>G	p.Asp60Glu	missense	Exon 3 of 15	NP_001308943.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PMS2	ENST00000265849.12	TSL:1 MANE Select	c.180C>G	p.Asp60Glu	missense	Exon 3 of 15	ENSP00000265849.7
PMS2	ENST00000382321.5	TSL:1	c.180C>G	p.Asp60Glu	missense	Exon 3 of 11	ENSP00000371758.4
PMS2	ENST00000406569.8	TSL:1	n.180C>G		non_coding_transcript_exon	Exon 3 of 13	ENSP00000514464.1

Frequencies

GnomAD3 genomes

AF:

0.000855

AC:

130

AN:

151978

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000664

AC XY:

475

AN XY:

715236

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

32872

American (AMR)

AF:

0.0000672

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

85370

European-Finnish (FIN)

AF:

0.00616

AC:

329

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4086

European-Non Finnish (NFE)

AF:

0.000602

AC:

656

AN:

1089282

Other (OTH)

AF:

0.000607

AC:

AN:

59326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000855

AC:

130

AN:

151978

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.0000968

AC:

AN:

41342

American (AMR)

AF:

0.000197

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00615

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68026

Other (OTH)

AF:

0.00191

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000731

Hom.:

Bravo

AF:

0.000359

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00101

AC:

123

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (6)

Hereditary cancer-predisposing syndrome (4)

Lynch syndrome 4 (3)

Breast and/or ovarian cancer (1)

Hereditary nonpolyposis colorectal neoplasms (1)

Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.18

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.80

M_CAP

Benign

0.071

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.011

MutationAssessor

Benign

-0.12

PhyloP100

-0.14

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.33

Sift

Benign

0.63

Sift4G

Benign

0.72

Polyphen

0.022

Vest4

0.37

MutPred

0.30

Loss of ubiquitination at K57 (P = 0.0997)

MVP

0.91

MPC

0.042

ClinPred

0.0074

GERP RS

1.3

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.11

gMVP

0.27

Mutation Taster

=90/10

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over