2-189795811-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000534.5(PMS1):c.175G>A(p.Glu59Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,613,856 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (15 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.07

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021964759).
• BP6: Variant 2-189795811-G-A is Benign according to our data. Variant chr2-189795811-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 708165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.175G>A	p.Glu59Lys	missense_variant	3/13	ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.175G>A	p.Glu59Lys	missense_variant	3/13	1	NM_000534.5	P1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00275 AC: 691 AN: 251432 Hom.: 3 AF XY: 0.00280 AC XY: 380 AN XY: 135892

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00467

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00383 AC: 5595 AN: 1461566 Hom.: 15 Cov.: 30 AF XY: 0.00381 AC XY: 2773 AN XY: 727110

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00460

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00250 AC: 380 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74474

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00459

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00378 Hom.: 2

Bravo AF: 0.00244

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00330 AC: 401

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

PMS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	19
Dann	Benign	0.89
DEOGEN2	Benign	0.19	T;T;T;T;T;.;T;T;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N
PrimateAI	Benign	0.37	T
Polyphen		0.034, 0.0020, 0.0090	.;B;B;B;B;.;.;.;.;.
Vest4		0.27, 0.31, 0.15, 0.32, 0.26, 0.21
MVP		0.91
MPC		0.066
ClinPred		0.0055	T
GERP RS		4.8
Varity_R		0.074
gMVP		0.35

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: rs143265397; hg19: chr2-190660537;