rs149202766

chr7-5977638-G-Achr7-5977638-G-Cchr7-5977638-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP4_Moderate BS2

The NM_000535.7(PMS2):c.2395C>T(p.Arg799Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,598,362 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts 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. R799Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (9 hom., cov: 30)
  • Exomes 𝑓: 0.00013 (3 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:4
• Conservation: PhyloP100: 2.73

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 -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.07591587).
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2395C>T	p.Arg799Trp	missense_variant	14/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2395C>T	p.Arg799Trp	missense_variant	14/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 208 AN: 149538 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.000540

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000512 AC: 122 AN: 238072 Hom.: 1 AF XY: 0.000387 AC XY: 50 AN XY: 129350

Gnomad AFR exome AF: 0.000661

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000380

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.000134 AC: 194 AN: 1448722 Hom.: 3 Cov.: 31 AF XY: 0.000133 AC XY: 96 AN XY: 720896

Gnomad4 AFR exome AF: 0.000482

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000281

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.00140 AC: 209 AN: 149640 Hom.: 9 Cov.: 30 AF XY: 0.00193 AC XY: 141 AN XY: 72880

Gnomad4 AFR AF: 0.000563

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000119

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000422 Hom.: 1

Bravo AF: 0.00123

ESP6500AA AF: 0.00142 AC: 6

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000158 AC: 19

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2021	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2395C>T, in exon 14 that results in an amino acid change, p.Arg799Trp. This sequence change has been described in the gnomAD database with a frequency of 0.31% in the Latino/Admixed American subpopulation including one homozygous individual (dbSNP rs149202766). The p.Arg799Trp change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Arg799Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been identified in individuals evaluated for Lynch syndrome, in an individual with pancreatic adenocarcinoma, and in individuals assessed for hereditary breast and ovarian cancer (PMID: 28449805, 28528518, 24072394, 2648339). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg799Trp change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2023	Variant summary: PMS2 c.2395C>T (p.Arg799Trp) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 238072 control chromosomes, predominantly at a frequency of 0.0031 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. Furthermore, the variant allele was found at a frequency of 0.001391 in 149538 control chromosomes, predominantly at a frequency of 0.01181 within the Latino subpopulation in the gnomAD (v3) database, including 9 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD (v3) database is approximately 107-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. This observation needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured, although the observation of at least 9 homozygotes, decreases the likelihood of a pseudogene artefact. c.2395C>T has been reported in the literature in sequencing studies of individuals affected with pancreatic cancer, Lynch Syndrome and hereditary breast and ovarian cancer syndrome (e.g. Cock-Rada_2017, Hu_2016, Li_2020, Oliver_2019, Sunga_2017, Yurgelun_2017, Zahary_2014). Specifically, Zahary_2014 reports the variant in one suspected Lynch syndrome patient who was indicated to have absent PMS2 protein expression, although the IHC findings from MLH1 and MSH2 were not provided. Furthermore, co-occurrence and cosegregation data and MLH1 gene testing results were not reported. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in a HBOC patient (BRCA1 c.1674delA, p.Gly559fsX13; Cock-Rada_2017), providing additional supporting evidence for a non-pathogenic role attributed to this variant. The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 26333163, 24072394, 28135145, 28528518, 28449805, 30122538, 31391288, 31921681, 35449176). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4), likely benign (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of Lynch syndrome-related cancers, at least one of whom had tumor studies consistent with pathogenic variants in this gene (Zahary 2014, Hu 2016, Sunga 2017, Yurgelun 2017, Cock-Rada 2018, Oliver 2019, Li 2020); This variant is associated with the following publications: (PMID: 24072394, 26483394, 26798439, 28135145, 26333163, 28528518, 30979843, 30122538, 31391288, 31921681, 28449805) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 07, 2023	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs:35449176 (2022), 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2, 31921681 (2019), 28528518 (2017)), colorectal cancer (PMIDs: 28135145 (2017), 28449805 (2017), 24072394 (2014)), and pancreatic cancer (PMID: 26483394 (2015)), as well as in unaffected individuals in a large breast cancer association study (PMIDs: 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2). The frequency of this variant in the general population, 0.0031 (108/34802 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 19, 2022	This missense variant replaces arginine with tryptophan at codon 799 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 24072394, 28135145, 28449805), breast/ovarian cancer (PMID: 28528518, 31921681 33471991), or pancreatic cancer (PMID: 26483394) This variant has been identified in 119/233620 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in multiple healthy control individuals (PMID: 33471991). This observed population allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 13, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ovarian cancer Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;.;.;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;.;D;.;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.076	T;T;T;T;T;T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.6	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.7	D;D;.;.;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.94
MVP		0.97
MPC		3.3
ClinPred		0.16	T
GERP RS		3.7
Varity_R		0.88
gMVP		0.89

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: rs149202766; hg19: chr7-6017269;