rs587781317

chr7-5982903-C-Gchr7-5982903-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000535.7(PMS2):c.2095G>C(p.Asp699His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D699E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000535.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 7-5982903-C-G is Pathogenic according to our data. Variant chr7-5982903-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2095G>C	p.Asp699His	missense_variant	12/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2095G>C	p.Asp699His	missense_variant	12/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447822 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719870

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: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 06, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMID: 23012243 (2013), 29345684 (2018), 31992580 (2020)), breast cancer (PMID: 24113346 (2014)), endometrial and ovarian cancer (PMID: 34357101 (2021)), and in other individuals tested for cancer predisposition (PMID: 20205264 (2010), 28514183 (2017)). The variant has also been reported in a homozygous individual affected with constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 23729388 (2013)). Functional studies indicated the variant was moderately functional and showed a borderline deficiency in the DNA damage response affecting cell viability (PMID: 28494185 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2023	Identified in the heterozygous state in patients with Lynch-related cancers or with a tumor demonstrating isolated loss of PMS2 expression via immunohistochemistry (Vaughn et al., 2010; Roberts et al., 2014; Wang et al., 2020); Published functional studies demonstrate a damaging effect: impaired MMR activity (Arora et al., 2017; D'Arcy et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25856668, 31391288, 24113346, 23012243, 31992580, 29345684, 20205264, 23729388, 28494185, 35189042, 18619468) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 13, 2021	PP3, PP4, PM2, PM3 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2023	The p.D699H variant (also known as c.2095G>C), located in coding exon 12 of the PMS2 gene, results from a G to C substitution at nucleotide position 2095. The aspartic acid at codon 699 is replaced by histidine, an amino acid with similar properties. This alteration was identified in several individuals whose family history met Amsterdam criteria (Ambry internal data). This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of PMS2 expression by immunohistochemistry (Ambry internal data). This alteration was also reported homozygous in a child with features suggestive of constitutional mismatch repair deficiency (CMMR-D); however, no tumor testing was performed (Walter AW et al. Pediatr Blood Cancer. 2013 Nov; 60(11):E135-6). In vitro studies have shown that the p.D699H variant exhibits expression levels similar to wildtype; however, protein function was reduced (Arora S et al. Cancer Biol. Ther. 2017 Jul;18:519-533). Based on internal structural analysis, this variant sits at the interface between PMS2/MutLa and is anticipated to result in a significant decrease in structural stability (Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr; 20(4):461-8). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 16, 2022	- -

Lynch syndrome 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 06, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35189042, 16873062, 18619468]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been observed homozygous in one or more individuals with Constitutional Mismatch Repair Deficiency Syndrome (CMMRD) [PMID: 23729388]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 25, 2023	- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 16, 2023

Variant summary: PMS2 c.2095G>C (p.Asp699His) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 221718 control chromosomes. c.2095G>C has been reported in the literature, including one patient whose tumors showed isolated loss of PMS2 by immunohistochemistry (Vaughn_2010), and in a child with constitutional mismatch repair deficiency who carried the variant in the homozygous state (Walter_2013). It has also been reported as a class 3 variant in an individual with MSI-high colorectal cancer and equivocal IHC analysis who underwent a comprehensive PMS2 analysis (example, Wang_2020). In addition, the variant has been reported in other patients being tested by various NGS cancer panels, without long-range PCR to confirm lack of pseudogene interference (Espenschied_2017, Goodenberger_2015, Mauer_2013, Roberts_2018, Li_2019). An in vitro functional study showed the variant to have proficient RNA expression and protein expression, with reduced viability leading authors to described the variant as moderately functional (Arora_2017). Another functional study demonstrated reduced mismatch repair capacity (MMR) as compared to wild-type (D'Arcy_2022). The following publications have been ascertained in the context of this evaluation (PMID: 28494185, 35189042, 28514183, 25856668, 31391288, 24113346, 29345684, 20205264, 23729388, 31992580). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 699 of the PMS2 protein (p.Asp699His). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with clinical features of Lynch syndrome or autosomal recessive constitutional mismatch repair deficiency (PMID: 20205264, 23012243, 23729388, 28514183; Invitae). ClinVar contains an entry for this variant (Variation ID: 140847). 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 expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PMS2 function (PMID: 28494185). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;D;.;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.9	D;D;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.98
MutPred		0.90		Loss of catalytic residue at D699 (P = 0.029);.;.;.;.;.;
MVP		0.98
MPC		3.5
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs587781317; hg19: chr7-6022534;