7-5987554-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000535.7(PMS2):c.1211C>G(p.Pro404Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,613,884 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. P404L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:1
• Conservation: PhyloP100: 1.90

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04062739).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1211C>G	p.Pro404Arg	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1211C>G	p.Pro404Arg	missense_variant	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000921 AC: 23 AN: 249858 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 157 AN: 1461650 Hom.: 0 Cov.: 34 AF XY: 0.000118 AC XY: 86 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152234 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 25, 2022	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.1211C>G, in exon 11 that results in an amino acid change, p.Pro404Arg. This sequence change has been previously described in individuals with colorectal cancer suspected Lynch syndrome, including some individuals whose tumors showed microsatellite instability or lack of PMS2 protein on immunohistochemistry (PMID: 19690142, 25980754, 26437257, 28874130, 30256826). This sequence change has been described in the gnomAD database with a global population frequency of 0.008% (dbSNP rs536111818). The p.Pro404Arg change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. The p.Pro404Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro404Arg change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2019	Variant summary: PMS2 c.1211C>G (p.Pro404Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 249858 control chromosomes. The observed variant frequency is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Non-Polyposis Colon Cancer phenotype (7.1e-05), however this data should be cautiously interpreted as PMS2 has highly homologous pseudogenes. c.1211C>G has been reported in the literature in individuals with suspected Lynch Syndrome and LS-associated cancers as well as breast cancer (daSilva_2015, Jelsig_2016, Kraus_2015, Mueller_2009, Rossi_2017, Yurgelun_2015), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	Observed in individuals with a personal or family history suspicious for Lynch syndrome, including those whose tumors revealed microsatellite instability or absence of PMS2 protein on immunohistochemistry (Mueller et al., 2009; Carneiro da Silva et al., 2015; Yurgelun et al., 2015; Martin-Morales et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19690142, 25980754, 26437257, 27146957, 28874130, 30256826) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 07, 2023	The frequency of this variant in the general population, 0.00033 (10/30614 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with or suspected of being affected with Lynch syndrome (PMID: 19690142 (2009), 25980754 (2015), 26437257 (2015), and 28874130 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS2 p.Pro404Arg variant was identified in 3 of 4424 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal cancer and a history of Lynch syndrome–associated cancer and/or polyps and was not identified in 368 control chromosomes from healthy individuals (Mueller 2009, Rossi 2017, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs536111818) as with uncertain significance allele and in the ClinVar and Clinvitae databases as uncertain significance by Ambry Genetics, Invitae, GeneDx, and Color Genomics. In addition, the variant was listed 1X in the Insight Colon Cancer Gene Variant and in the Insight Hereditary Tumors databases. The variant was not identified in the GeneInsight-COGR, Cosmic, MutDB, Zhejiang University, and Mismatch Repair Genes Variant databases; nor was it identified in the NHLBI GO Exome Sequencing Project. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004). The variant was identified in control databases in 22 of 276462 chromosomes at a frequency of 0.0001 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: African in 1 of 23802 chromosomes (freq: 0.00004), Latino in 3 of 34416 chromosomes (freq: 0.00009), European Non-Finnish in 8 of 126236 chromosomes (freq: 0.00006), and South Asian in 10 of 30782 chromosomes (freq: 0.0003) while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Pro404 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2023	The p.P404R variant (also known as c.1211C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1211. The proline at codon 404 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in a family who met Amsterdam I criteria (Martin-Morales L et al. PLoS One 2018 Sep;13:e0203885). In an analysis of 71 colorectal cancer patients, this alteration was detected in a suspected HNPCC/Lynch syndrome patient whose tumor demonstrated microsatellite instability (MSI-H) (Mueller J et al. Cancer Res. 2009 Sep;69:7053-61). This alteration has also been reported in a Brazilian individual with colorectal cancer whose tumor showed loss of MLH1 and PMS2 on immunohistochemistry analysis and whose family met Amsterdam I criteria (Carneiro da Silva F et al. PLoS ONE. 2015 Oct;10:e0139753). Another study reported this alteration in an individual who was found to have a single juvenile polyp removed at age 48, and this alteration was classified as likely not pathogenic (Jelsig AM et al. Scand. J. Gastroenterol. 2016 Sep;51:1118-25). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2023	This missense variant replaces proline with arginine at codon 404 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 25980754, 26437257, 28874130), breast cancer (PMID: 36200007), or juvenile polyposis (PMID: 27146957). This variant has been identified in 24/281242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Lynch syndrome 4 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 26, 2022	The PMS2 c.1211C>G (p.Pro404Arg) missense change has a maximum subpopulation frequency of 0.033% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer and/or Lynch syndrome (PMID: 19690142, 25980754, 26437257, 28135145, 28874130, 30256826). In one of these individuals the tumor demonstrated microsatellite instability (PMID: 19690142) and in a different individual the tumor revealed loss of the MLH1/PMS2 complex (PMID: 26437257). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

PMS2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2022

The PMS2 c.1211C>G variant is predicted to result in the amino acid substitution p.Pro404Arg. This variant has been reported in patients with suspected Lynch syndrome (Mueller et al. 2009. PubMed ID: 19690142; Jelsig et al. 2016. PubMed ID: 27146957 ). This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6027185-G-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142875/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces proline with arginine at codon 404 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 not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 25980754, 26437257, 28874130) or juvenile polyposis (PMID: 27146957). This variant has been identified in 24/281242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.18	T;.;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.75	T;T;.;T;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.041	T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.1	D;D;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.039	D;D;.;.;.
Sift4G	Benign	0.20	T;T;.;.;.
Polyphen		0.13	B;P;.;.;P
Vest4		0.19
MVP		0.63
MPC		0.041
ClinPred		0.13	T
GERP RS		4.4
Varity_R		0.046
gMVP		0.25

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: rs536111818; hg19: chr7-6027185;