2-189854881-G-A

Position:

chr2-189854881-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000534.5(PMS1):c.1609G>A(p.Glu537Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00243 in 1,607,300 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 6 hom. )

Consequence

PMS1
NM_000534.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 3.85

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:

LOC105373796 (HGNC:):

LOC105373796 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070312917).

BP6

Variant 2-189854881-G-A is Benign according to our data. Variant chr2-189854881-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS1	NM_000534.5 linkuse as main transcript	c.1609G>A	p.Glu537Lys	missense_variant	9/13	ENST00000441310.7	NP_000525.1
LOC105373796	XR_001739151.2 linkuse as main transcript	n.319-2024C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7 linkuse as main transcript	c.1609G>A	p.Glu537Lys	missense_variant	9/13	1	NM_000534.5	ENSP00000406490	P1	P54277-1

Frequencies

GnomAD3 genomes

AF:

0.00207

AC:

314

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00219

AC:

546

AN:

249024

Hom.:

AF XY:

0.00224

AC XY:

302

AN XY:

135038

show subpopulations

Gnomad AFR exome

AF:

0.000513

Gnomad AMR exome

AF:

0.00297

Gnomad ASJ exome

AF:

0.00988

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000197

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00280

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00247

AC:

3591

AN:

1455162

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1764

AN XY:

724140

show subpopulations

Gnomad4 AFR exome

AF:

0.000542

Gnomad4 AMR exome

AF:

0.00344

Gnomad4 ASJ exome

AF:

0.0114

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00266

Gnomad4 OTH exome

AF:

0.00224

GnomAD4 genome

AF:

0.00206

AC:

313

AN:

152138

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

144

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000747

Gnomad4 AMR

AF:

0.00282

Gnomad4 ASJ

AF:

0.00952

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00291

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00294

Hom.:

Bravo

AF:

0.00214

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00443

AC:

ExAC

AF:

0.00188

AC:

228

EpiCase

AF:

0.00289

EpiControl

AF:

0.00356

ClinVar

Significance: Likely benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS1 p.Glu361Lys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs151325573) and ClinVar (classified as a VUS by Illumina and Genomic Research Center, Shahid Beheshti University of Medical Sciences for Lynch Syndrome). The variant was identified in control databases in 596 of 280400 chromosomes (3 homozygous) at a frequency of 0.002126 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: Ashkenazi Jewish in 101 of 10314 chromosomes (freq: 0.009793), Latino in 103 of 35214 chromosomes (freq: 0.002925), European (non-Finnish) in 354 of 128070 chromosomes (freq: 0.002764), Other in 18 of 7128 chromosomes (freq: 0.002525), African in 13 of 24308 chromosomes (freq: 0.000535), South Asian in 6 of 30404 chromosomes (freq: 0.000197) and European (Finnish) in 1 of 25054 chromosomes (freq: 0.00004); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu361 residue is not conserved in mammals and four out of five computational analyses (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. 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. -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2021	- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

T;T;T;T;T;.;.;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.92

D;.;D;D;D;D;D;D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.0070

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.5

.;.;.;.;M;.;M;.;.

MutationTaster

Benign

0.95

D;D;D;D;D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.97

.;.;N;.;N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.050

.;.;D;.;T;T;T;D;T

Sift4G

Benign

0.24

.;T;T;T;T;T;T;T;T

Polyphen

0.93, 0.89

.;.;.;P;P;.;.;.;.

Vest4

0.27, 0.27, 0.32, 0.30, 0.34, 0.29

MVP

0.99

MPC

0.16

ClinPred

0.039

GERP RS

5.0

Varity_R

0.073

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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