rs2066459

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000534.5(PMS1):c.605G>A(p.Arg202Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,946 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 11 hom., cov: 31)

Exomes 𝑓: 0.012 ( 158 hom. )

Consequence

PMS1
NM_000534.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 2.33

Variant links:

Genes affected

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

PMS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005322993).

BP6

Variant 2-189843986-G-A is Benign according to our data. Variant chr2-189843986-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00788 (1201/152318) while in subpopulation SAS AF= 0.0207 (100/4824). AF 95% confidence interval is 0.0174. There are 11 homozygotes in gnomad4. There are 584 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5 link	c.605G>A	p.Arg202Lys	missense_variant	Exon 6 of 13	ENST00000441310.7	NP_000525.1	P54277-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7 link	c.605G>A	p.Arg202Lys	missense_variant	Exon 6 of 13	1	NM_000534.5	ENSP00000406490.3		P54277-1

Frequencies

GnomAD3 genomes

AF:

0.00791

AC:

1204

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00785

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0113

AC:

2842

AN:

251238

Hom.:

AF XY:

0.0122

AC XY:

1662

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0238

Gnomad FIN exome

AF:

0.00254

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0117

AC:

17167

AN:

1461628

Hom.:

158

Cov.:

AF XY:

0.0120

AC XY:

8742

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.00691

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0236

Gnomad4 FIN exome

AF:

0.00294

Gnomad4 NFE exome

AF:

0.0120

Gnomad4 OTH exome

AF:

0.0123

GnomAD4 genome

AF:

0.00788

AC:

1201

AN:

152318

Hom.:

Cov.:

AF XY:

0.00784

AC XY:

584

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00190

Gnomad4 AMR

AF:

0.00777

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0207

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0129

Hom.:

Bravo

AF:

0.00778

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.0120

AC:

1461

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0146

ClinVar

Significance: Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS1 p.Arg202Lys variant was identified in a study by Bodian et al. (2014) which reports that this variant falls on the portion of the protein distal to the DNA-binding site and is likely to have weaker effects on protein function and hence cancer risk. The variant was identified in dbSNP (ID: rs2066459) as "With Uncertain significance allele". In ClinVar, the variant was classified as uncertain significance by three submitters: Illumina, Genomic Research Center (Shahid Beheshti University of Medical Sciences) and ITMI. The associated conditions are Lynch syndrome and hereditary breast and ovarian cancer syndrome. The variant was found in the LOVD 3.0 database, however it was not identified in Cosmic. The variant was identified in control databases in 3077 of 282642 chromosomes (26 homozygous) at a frequency of 0.010887 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 727 of 30610 chromosomes (freq: 0.02375), Other in 104 of 7214 chromosomes (freq: 0.01442), Ashkenazi Jewish in 148 of 10362 chromosomes (freq: 0.01428), European (non-Finnish) in 1758 of 129018 chromosomes (freq: 0.01363), Latino in 228 of 35426 chromosomes (freq: 0.006436), European (Finnish) in 63 of 25096 chromosomes (freq: 0.00251), African in 47 of 24970 chromosomes (freq: 0.001882), East Asian in 2 of 19946 chromosomes (freq: 0.0001). The variant was also identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium (August 8th 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Arg202 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0097

T;T;T;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.014

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.57

.;T;T;T;T

MetaRNN

Benign

0.0053

T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.55

.;.;N;N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.39

.;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.59

.;T;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.0010

.;.;B;.;.

Vest4

0.064

MPC

0.062

ClinPred

0.011

GERP RS

5.1

Varity_R

0.12

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over