7-5982849-C-T

Position:

• chr7-5982849-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000535.7(PMS2):​c.2149G>A​(p.Val717Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,608,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00071 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:18
• Conservation: PhyloP100: 1.07

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]

PMS2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02527678).
• BP6: Variant 7-5982849-C-T is Benign according to our data. Variant chr7-5982849-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41709.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=14, Uncertain_significance=6, Benign=3}. Variant chr7-5982849-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2149G>A	p.Val717Met	missense_variant	12/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2149G>A	p.Val717Met	missense_variant	12/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.000706 AC: 107 AN: 151632 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00722

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000758 AC: 180 AN: 237492 Hom.: 1 AF XY: 0.000759 AC XY: 98 AN XY: 129040

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000758

Gnomad ASJ exome AF: 0.00699

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.000666 AC: 971 AN: 1456952 Hom.: 1 Cov.: 31 AF XY: 0.000682 AC XY: 494 AN XY: 724746

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000878

Gnomad4 ASJ exome AF: 0.00783

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000584

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000705 AC: 107 AN: 151750 Hom.: 1 Cov.: 31 AF XY: 0.000647 AC XY: 48 AN XY: 74190

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00722

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.000782

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000635 AC: 77

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2023	Variant summary: PMS2 c.2149G>A (p.Val717Met) results in a conservative amino acid change located in the C-terminal dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 237678 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome phenotype (7.1e-05), strongly suggesting that the variant is benign. c.2149G>A has been reported in the literature in individuals affected with Lynch Syndrome and other tumor phenotypes, however these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome (example, Brea-Fernandez_2013, Borras_2013, Shirts_2015, Tung_2016, Yurgelun_2017, Pearlman_2017, Gonzalez-Acosta_2017, Chan_2018, Martin-Morales_2018, Delahunty_2022, Liccardo_2022). In at least one family, the variant did not segregate with the disease and co-occurred with another PMS2 variant (c.2444C>T). Functional studies by these authors showed that a different variant, c.2444C>T (p.S815L) caused a significant decrease in PMS2 and MLH1 protein expression (~15% of normal) and impaired MMR activity (~10% of normal). The variant of interest was also functionally analyzed and found not to significantly impair protein expression or MMR activity (Gonzalez-Acosta 2017), suggesting the variant of interest is likely not the driver of disease in the family. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Multiple other co-occurrences with pathogenic variants have been reported in the literature and observed at our laboratory (example, Pearlman_2017 - MLH1 c.589-2A>G; our laboratory - PMS2 c.1831dupA, p.Ile611fsX2), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 34371384, 23709753, 23837913, 30093976, 35263119, 28365877, 22703879, 35475445, 30256826, 27978560, 26845104, 26976419, 28135145). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 reporting the variant with conflicting assessments (benign/likely benign, n=14; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 23, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 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. -

Lynch syndrome Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 31, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PMS2 p.Val717Met variant was identified in 3 of 1014 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome and breast cancer (Brea-Fernandez 2014, Tung 2016). The variant was also identified in dbSNP (ID: rs201671325) as “With other allele”, ClinVar (7x, as likely benign by GeneDx, Invitae, as uncertain significance by Ambry Genetics, university of Washington, The Children Hospital of Philadelphia, Counsyl and Biescker Lab), Clinvitae (5x, as likely benign and uncertain significance), Cosmic (1x, as neutral in Haematopoitic and lymphoid tissue), Insight Colon Cancer Gene Variant Database (1x, unknown pathogenicity), Insight Hereditary Tumor Database (1x). The variant was identified in control databases in 184 of 263616 chromosomes at a frequency of 0.0007 in the following populations: African in 1 of 22146 chromosomes (freq. 0.000045), other in 6 of 6242 chromosomes (freq. 0.00096), Latino in 25 of 32882 chromosomes (freq. 0.00076), European in 81 of 119490 chromosomes (freq. 0.00067), Ashkenazi Jewish in 70 of 9812 chromosomes (freq. 0.007) and Finnish in 1 of 24924 chromosomes (freq. 0.00004),increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Consortium Feb 27, 2017). The p.Val717 residue is 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. A Comprehensive functional study, including segregation data on two co-occurring in trans PMS2 variants (c.2149G>A, p.Val717Met and c.2444C>T, p.Ser815Lys) in a Spanish patient with family history of Lynch syndrome, concluded that p.Val717Met variant is likely benign and the p.Ser815Lys variant is likely pathogenic in this family (Gonzalez 2017).The variant is located within the MutL C-terminal, and dimerisation functional domain. 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 likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Oct 12, 2018	The PMS2 variant designated as NM_000059.3:c.2149C>T (p.Val470Met) is classified as likely benign. This variant has been reported at a frequency of 1 in 70 individuals with Ashkenazi Jewish ancestry, and it is present in multiple ethnic populations (gnomad.broadinstitute.org). Variants present at this population frequency are unlikely to be associated with high penetrance hereditary cancer risk. This variant has also been seen in an individual with a co-occurring pathogenic mutation, adding evidence that it is benign. This variant is in ClinVar (Variation ID: 41709) and has been classified as likely benign by other clinical laboratories. Bayesian analysis integrating all of this data (Tavtigian et al, 2018) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter PMS2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Likely benign, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 04, 2024	The following ACMG criteria is used: BS1. The variant is reported once in gnomAD in homozygote state. Functional analysis indicates that the variant does not affect the function of PMS2 (PMID: 28365877) -

Lynch syndrome 4 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 17, 2018	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. -

not provided Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PMS2: PP2, BS2 -

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

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 03, 2023

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.86	D;D;.;D;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.025	T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N;N;.;.;.;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.010	D;D;.;.;.;T
Sift4G	Uncertain	0.054	T;D;.;.;.;T
Polyphen		0.98	D;D;.;.;D;D
Vest4		0.49
MVP		0.78
MPC		2.2
ClinPred		0.087	T
GERP RS		3.8
Varity_R		0.28
gMVP		0.35

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: rs201671325; hg19: chr7-6022480; COSMIC: COSV56221991; COSMIC: COSV56221991;