chr7-5992000-C-T

Position:

chr7-5992000-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000535.7(PMS2):c.961G>A(p.Val321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,598,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V321A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 2.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14770451).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.961G>A	p.Val321Ile	missense_variant	9/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.961G>A	p.Val321Ile	missense_variant	9/15	1	NM_000535.7	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251270

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000353

AC:

AN:

1446044

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

720456

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.0000374

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with endometrial or colorectal cancer, some with tumors demonstrating isolated loss of PMS2 and/or microsatellite instability (PMID: 20205264, 25871621, 31992580); This variant is associated with the following publications: (PMID: 20205264, 25871621, 31391288, 31992580, 11574484) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2023	The p.V321I variant (also known as c.961G>A), located in coding exon 9 of the PMS2 gene, results from a G to A substitution at nucleotide position 961. The valine at codon 321 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown pathogenicity in one individual from a cohort of 145 unrelated patient samples submitted for PMS2 whole gene analysis. Additionally, authors note that this individual's tumor exhibited isolated loss of PMS2 expression by immunohistochemistry (IHC) (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93). The alteration was also detected in the germline of a 54-year-old male diagnosed with two ascending colorectal cancers; both tumors exhibited isolated loss of PMS2 by IHC and high microsatellite instability (MSI-H), but this individual did not meet Amsterdam II criteria (Dudley B et al. Am. J. Surg. Pathol., 2015 Aug;39:1114-20). Additionally, this alteration was identified in an individual diagnosed with uterine cancer at 63. This individual's tumor exhibited loss of PMS2 expression by IHC (Wang Q et al. J Med Genet, 2020 07;57:487-499). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2015	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 03, 2022

Variant summary: PMS2 c.961G>A (p.Val321Ile) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal (IPR002099) of the encoded protein sequence. Four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251270 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.961G>A has been reported in the literature in affected individuals whose tumors exhibited isolated loss of PMS2 expression by immunohistochemistry without strong evidence for causality (Dudley_2015, Vaughn_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

PMS2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2024

The PMS2 c.961G>A variant is predicted to result in the amino acid substitution p.Val321Ile. This variant has been reported in individuals suspected to have Lynch syndrome, most of whom had tumors with isolated loss of PMS2 immunohistochemical expression (Wang et al. 2020. PubMed ID: 31992580). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD. Another nucleotide change affecting this amino acid (p.Val321Ile) has been reported in an individual with colorectal cancer (Jiang et al. 2019. PubMed ID: 30521064). This variant has conflicting interpretations of uncertain significance and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141713/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 321 of the PMS2 protein (p.Val321Ile). This variant is present in population databases (rs377043696, gnomAD 0.02%). This missense change has been observed in individual(s) with Lynch syndrome-associated cancer (PMID: 20205264, 25871621, 31992580). ClinVar contains an entry for this variant (Variation ID: 141713). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Lynch syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.15

T;.;.;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;.;D;.

M_CAP

Benign

0.015

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.2

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.49

N;N;.;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.24

T;T;.;.;.

Sift4G

Benign

0.57

T;T;.;.;.

Polyphen

0.037

B;B;.;.;B

Vest4

0.27

MVP

0.81

MPC

0.090

ClinPred

0.065

GERP RS

4.5

Varity_R

0.087

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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