rs587780046

chr7-5982986-G-Achr7-5982986-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000535.7(PMS2):c.2012C>T(p.Thr671Met) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,515,790 control chromosomes in the GnomAD database, including 1 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. T671A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:20 B:3 O:1
• Conservation: PhyloP100: 5.70

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 -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000535.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.17239493).
• BP6: Variant 7-5982986-G-A is Benign according to our data. Variant chr7-5982986-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127770.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=18, Benign=2, not_provided=1}. Variant chr7-5982986-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2012C>T	p.Thr671Met	missense_variant	12/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2012C>T	p.Thr671Met	missense_variant	12/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151324 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000190 AC: 32 AN: 168512 Hom.: 0 AF XY: 0.000219 AC XY: 20 AN XY: 91418

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000155

Gnomad SAS exome AF: 0.0000849

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000234 AC: 319 AN: 1364466 Hom.: 1 Cov.: 22 AF XY: 0.000249 AC XY: 169 AN XY: 678008

Gnomad4 AFR exome AF: 0.0000332

Gnomad4 AMR exome AF: 0.0000260

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000187

Gnomad4 SAS exome AF: 0.0000620

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.0000884

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151324 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 11 AN XY: 73844

Gnomad4 AFR AF: 0.0000489

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000953

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.000180 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:20 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 13, 2023	The frequency of this variant in the general population, 0.00035 (29/83638 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with pancreatic cancer (PMIDs: 26483394 (2015) and 27449771 (2016)), breast cancer (PMIDs: 25186627 (2015), 29785153 (2018), 31159747 (2019), 31422574 (2019), 33120919 (2020), 35402282 (2022)), and colorectal cancer (PMIDs: 28135145 (2017), 34271781 (2021)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (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, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 04, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26483394, 31422574, 22229248, 27449771, 28135145, 29101607, 29785153, 25186627, 31159747, 30613976, 34271781, 33120919, 26321251, 35372080, 35402282, 30113427, 35089076, 33471991, 11292842, 37534630, 35263119, 34326862) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS2 p.Thr671Met variant was identified in 3 of 260 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer of Romanian ethnicity (Goidescu 2017). The variant was also identified in dbSNP (ID: rs587780046) as with uncertain significance allele; and in ClinVar and Clinvitae databases as benign by Ambry Genetics and uncertain significance by Invitae, Praxis fuer Humangenetik Tuebingen, Quest Diagnostics - Nichols Institute San Juan Capistrano, Fulgent Genetics, GeneDx and Pathway Genomics. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 34 of 195042 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 3 of 5030 chromosomes (freq: 0.0006), European Non-Finnish in 27 of 81252 chromosomes (freq: 0.0003), East Asian in 2 of 13498 chromosomes (freq: 0.0001), and South Asian in 2 of 23600 chromosomes (freq: 0.0001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish, populations. The p.Thr671 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Lynch syndrome 4 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 17, 2022	The PMS2 c.2012C>T (p.Thr671Met) missense change has a maximum subpopulation frequency of 0.035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-6022617-G-A?dataset=gnomad_r2_1). This variant is located in exon 12 of the PMS2 gene and data in this region are not considered reliable due to high pseudogene homology. This variant was reported in 2 of 1,058 individuals with colorectal cancer (PMID: 28135145). One of the individuals also harbored a pathogenic germline variant in MUTYH (c.891+3A>C). The tumor of this individual was determined to be MMR proficient and microsatellite stable (PMID: 28135145). This variant has also been reported in individuals with breast cancer (PMID: 25186627, 29785153, 30613976) and pancreatic cancer (PMID: 26483394, 27449771). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: not criteria met. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 12, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 18, 2022	- -

Hereditary cancer-predisposing syndrome Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 11, 2015	This alteration is classified as 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 02, 2023	This missense variant replaces threonine with methionine at codon 671 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 reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 25186627, 29785153, 31422574, 33120919), colorectal (PMID: 28135145), or pancreatic cancer (PMID: 2648339). This variant has been identified in 35/199754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable, because 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 22, 2022	- -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2024	Variant summary: PMS2 c.2012C>T (p.Thr671Met) 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 0.00019 in 168512 control chromosomes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05). However, this PMS2 locus is highly homologous to PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. c.2012C>T has been reported in the literature in individuals affected with breast cancer, colorectal cancer, ovarian cancer or pancreatic cancer (e.g. Tung 2015, Hu 2016, Yang 2016, Yurgelun 2017, Goidescu 2018, Rizzolo_2019, Tsaousis_2019, Duzkale_2021, Sahin_2022, Abdel-Razeq_2022, Dorling_2021, Delahunty_2022,) but has also been reported in individual(s) without a cancer diagnosis (e.g. Kraemer_2019). One of the reported colorectal cancer patients had a co-occurring pathogenic variant (KRAS c.34G>T, p.Gly12Cys) while the patient's tumor was determined to be MMR proficient and microsatellite stable (Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. 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: 35402282, 35263119, 33471991, 34271781, 29785153, 35372080, 26483394, 31422574, 30613976, 35089076, 31159747, 25186627, 27449771, 28135145, 33120919, 30113427). ClinVar contains an entry for this variant (Variation ID: 127770). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 09, 2021	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2012C>T, in exon 12 that results in an amino acid change, p.Thr671Met. This sequence change has been described in gnomAD with a frequency of 0.035% in the Non-Finnish European sub-population (dbSNP rs587780046). The p.Thr671Met change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr671Met substitution. The c.2012C>T sequence change has been reported in the literature in individuals affected with breast cancer, colorectal cancer or pancreatic cancer (PMIDs: 25186627, 26483394, 27449771, 28135145, 29785153, 30613976, 31159747) but has also been reported in individuals without a cancer diagnosis (PMID: 31422574). One of the reported colorectal cancer patients also carried a pathogenic variant in the KRAS gene (c.34G>T, p.Gly12Cys). The patient's tumor was determined to be MMR proficient and microsatellite stable (PMID: 28135145). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr671Met change remains unknown at this time. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 04, 2022

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Lynch syndrome 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 07-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;.;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N;N;.;.;.;N
REVEL	Benign	0.11
Sift	Uncertain	0.028	D;D;.;.;.;D
Sift4G	Uncertain	0.026	D;D;.;.;.;T
Polyphen		0.84	P;P;.;.;P;D
Vest4		0.29
MVP		0.92
MPC		2.6
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.041
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs587780046; hg19: chr7-6022617; COSMIC: COSV105056420;