rs63750534

chr7-5987033-G-Achr7-5987033-G-Cchr7-5987033-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000535.7(PMS2):c.1732C>T(p.Arg578Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R578H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 0.752

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_000535.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.16515586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1732C>T	p.Arg578Cys	missense_variant	11/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1732C>T	p.Arg578Cys	missense_variant	11/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	Variant summary: PMS2 c.1732C>T (p.Arg578Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1732C>T has been reported in the literature in association with another PMS2 variant reported as c.1730_1731insA [ later annotated as c.1730dupA (p.Arg578Alafs*3)] in two siblings affected with features of Constitutional Mismatch Repair Deficiency (CMMRD) (Auclair_2007). The authors reported the combined variation as p.Lys577fs attributed to a gene conversion event. A different paternally inherited putatively pathogenic PMS2 variant (c.137G>T, p.Ser461Ile) in trans with this combined variant was attributed to be the cause of CMMRD in this family. This variant has also been reported in isolation as a VUS in an individual with colorectal cancer diagnosed at age 34 and an absent staining for MLH1 and PMS2 with intact staining for MSH2 and MSH6 proteins by Immunohistochemistry (example, Wang_2020). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17557300, 31992580). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2023	This missense variant replaces arginine with cysteine at codon 578 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 an individual affected with early onset colorectal cancer that displayed loss of MLH1 and PMS2 proteins via immunohistochemistry analysis (PMID: 31992580). This variant, alongside the variant c.1730_1731insA in cis, has also been reported in two siblings affected with constitutional mismatch repair deficiency who had another PMS2 variant c.137G>T (p.Ser46Ile) in trans (PMID: 17557300). This variant has been identified in 1/251352 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 2023	The p.R578C variant (also known as c.1732C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1732. The arginine at codon 578 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with features consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome and biallelic PMS2 mutations (Auclair J et al, Hum. Mutat. 2007 Nov; 28(11):1084-90). This variant was also identified in an individual with colorectal cancer diagnosed at age 34 whose tumor demonstrated loss of MLH1 and PMS2 protein expression by IHC (Wang Q et al. J Med Genet, 2020 07;57:487-499), and in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is not well 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. -

Lynch syndrome 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The PMS2 p.Arg578Cys variant was identified in the literature, although the frequency of this variant in an affected population was not provided (Auclair 2007, Wernstedt 2012). The variant was also identified in dbSNP (ID: rs63750534) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by InSight and Counsyl), Cosmic (3x in Endometrium, Large intestine, Skin), MutDB, and Insight Hereditary Tumors Database (1x class3). The variant was not identified in GeneInsight-COGR or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 1 of 246198 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in Latino population in 1 of 33582 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, East Asian, European, or South Asian populations. The p.Arg578 residue is conserved across mammals and other organisms, and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2020

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer with MLH1 and PMS2 absent on immunohistochemistry (Wang 2020); This variant is associated with the following publications: (PMID: 17557300, 31992580) -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 578 of the PMS2 protein (p.Arg578Cys). This variant is present in population databases (rs63750534, gnomAD 0.003%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency (CMMR-D)-associated tumors, breast cancer and colorectal cancer (PMID: 17557300, 31992580, 35449176). ClinVar contains an entry for this variant (Variation ID: 91311). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.32	T;.;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T;T;.;T;.
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.9	D;D;.;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;D;.;.;.
Sift4G	Uncertain	0.017	D;D;.;.;.
Polyphen		0.31	B;P;.;.;P
Vest4		0.39
MutPred		0.40		Gain of helix (P = 0.0078);.;.;.;.;
MVP		0.49
MPC		0.053
ClinPred		0.22	T
GERP RS		1.9
Varity_R		0.24
gMVP		0.32

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: rs63750534; hg19: chr7-6026664; COSMIC: COSV56221191;