NM_000535.7:c.2002A>G

Variant names:

• chr7-5986763-T-C
• rs869320619
• NM_000535.7:c.2002A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000535.7(PMS2):​c.2002A>G​(p.Ile668Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I668M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.10
• Publications: 15 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-5986763-T-C is Pathogenic according to our data. Variant chr7-5986763-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 192316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2002A>G	p.Ile668Val	missense_variant	Exon 11 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2002A>G	p.Ile668Val	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 30, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on splicing resulting in an abnormal transcript that is subject to nonsense mediated decay (Li et al., 2015; Biswas et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34489406, 34330892, 25691505, 33535600) -

Dec 28, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. The gain of a new splice site is predicted. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 15, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with valine at codon 668 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing by creating a new splice donor site 5 nucleotides upstream from the native intron 11 splice donor site. A functional study using cells from a carrier individual has shown that the cryptic donor site is utilized, and the aberrant splicing product results in a premature protein truncation (PMID: 25691505). However, the study also observed small amounts of full-length transcript were also produced from the mutant allele, indicating the leakiness of the cryptic donor site. These full-length transcripts were observed in association with functional partner MLH1 protein. The splicing defect has also been observed in a mouse-model with the mouse equivalent variant, c.1993A>G (PMID: 36715493). This variant occurs at a high frequency in the Canadian Inuit population with estimated heterozygote frequency of 1 in 16 (PMID: 25691505). This study included 13 homozygotes and 38 heterozygotes from 7 unrelated families, where the median age at primary cancer diagnosis associated with constitutional mismatch repair deficiency among the 13 homozygotes was 22 years old. In contrast, the median age of onset is 8 years old in individuals carrying different bi-allelic truncating variants. Another study has shown that affected homozygous carriers had relatively low microsatelite instability (PMID: 36586540). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant occurs at a high frequency in the Inuit population and has been associated with adult-onset cancers in homozygous individuals. However, this variant has not been reported in heterozygous individuals affected with PMS2-related cancers. Presence of the full-length transcript at low levels has been hypothesized as a mechanism for an attenuated phenotype in homozygous individuals. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jan 02, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2002A>G variant (also known as p.I668V), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 2002. The isoleucine at codon 668 is replaced by valine, an amino acid with highly similar properties. This variant has been identified in the homozygous state in individual(s) with features consistent with PMS2-related constitutional mismatch repair deficiency (Li L et al. J Med Genet, 2015 May;52:348-52; Shuen AY et al. J Clin Oncol, 2019 Feb;37:461-470; Biswas K et al. Cell Death Dis, 2021 Sep;12:838). Functional studies have demonstrated that this variant results in abnormal splicing through use of an alternate donor (Li L et al. J Med Genet, 2015 May;52:348-52). This variant has been described as a founder mutation in the Inuit population (Li L et al. J Med Genet, 2015 May;52:348-52). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Mismatch repair cancer syndrome 4 Pathogenic:1

May 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 668 of the PMS2 protein (p.Ile668Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency (CMMRD) (PMID: 25691505, 33535600). It is commonly reported in individuals of Inuit ancestry (PMID: 25691505, 33535600). ClinVar contains an entry for this variant (Variation ID: 192316). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. Studies have shown that this missense change results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 25691505, 34489406). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1

Feb 10, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4 Pathogenic:1

Sep 21, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 25691505, 34489406]. Functional studies indicate this variant impacts protein function [PMID: 25691505, 34489406, 30608896]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25691505, 33535600, 30608896, 36586540]. -

Lynch syndrome 1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;D;.
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.
PhyloP100		7.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.75	N;N;.;.;.
REVEL	Benign	0.13
Sift	Benign	0.19	T;T;.;.;.
Sift4G	Benign	0.066	T;T;.;.;.
Polyphen		0.57	P;D;.;.;D
Vest4		0.65
MutPred		0.27		Gain of catalytic residue at I668 (P = 0.0942);.;.;.;.;
MVP		0.57
MPC		2.9
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.16
gMVP		0.32
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 1
DS_DL_spliceai		0.49		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869320619; hg19: chr7-6026394;