7-5987328-G-C

Position:

• chr7-5987328-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000535.7(PMS2):​c.1437C>G​(p.His479Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,613,972 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0055 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (18 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:23 O:1
• Conservation: PhyloP100: 0.199

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054139197).
• BP6: Variant 7-5987328-G-C is Benign according to our data. Variant chr7-5987328-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41701.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, not_provided=1, Benign=12}. Variant chr7-5987328-G-C is described in Lovd as [Benign]. Variant chr7-5987328-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1437C>G	p.His479Gln	missense_variant	11/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1437C>G	p.His479Gln	missense_variant	11/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 834 AN: 152148 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00990

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00424 AC: 1067 AN: 251466 Hom.: 6 AF XY: 0.00432 AC XY: 587 AN XY: 135902

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.000815

Gnomad SAS exome AF: 0.00314

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00323 AC: 4718 AN: 1461706 Hom.: 18 Cov.: 39 AF XY: 0.00334 AC XY: 2430 AN XY: 727146

Gnomad4 AFR exome AF: 0.00920

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.00306

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00279

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152266 Hom.: 7 Cov.: 31 AF XY: 0.00560 AC XY: 417 AN XY: 74432

Gnomad4 AFR AF: 0.00970

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00990

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00345 Hom.: 1

Bravo AF: 0.00481

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00976 AC: 43

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00455 AC: 552

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:23 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PMS2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	This variant is associated with the following publications: (PMID: 27616075, 24728327, 28874130, 31433215, 31332305) -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2017	Variant summary: The PMS2 c.1437C>G (p.His479Gln) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome. This was confirmed by a functional study that showed through an in vitro MMR assay that the H479Q mutant protein has significantly higher relative repair efficiency than repair-deficient control E705K (70 vs 10%, p<0.01) (Drost_2013). This variant was found in 1284/277610 control chromosomes (8 homozygotes) at a frequency of 0.0046252, which is approximately 41 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in patients where it was often reported as a benign polymorphism. However, the frequency in ExAC and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between PMS2 and its overlapping pseudogenes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Also, in multiple internal LCA samples this variant was found to co-occur with other pathogenic variants: MSH2, c.942+3A>T, BRCA1, c.68_69delAG (p.Glu23fsX17), and BRCA2, c.5946delT (p.Ser1982fsX22). One study reports the variant in a sample that was IHC-negative for MLH1 and PMS2 and with observed MLH1 hypermethylation (van der Klift_2016). Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 20, 2023	- -

Lynch syndrome 4 Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 13, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Apr 14, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 19, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 09, 2018	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. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 08, 2021

- -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS2 p.His479Gln variant was identified in 9 of 2670 proband chromosomes (frequency: 0.003) from individuals or families with CRC and MSI positive tumors (Johnston 2012, Basil 1999, Wang 1999, Berginc 2009). The variant was also identified in the following databases: dbSNP (ID: rs63750685) as “With Likely benign, Uncertain significance allele”, ClinVar (5x, as benign by GeneDx, Invitae, Ambry Genetics, Prevention Genetics, NIH, 2x, uncertain significance by InSight, University of Washington, 1x, with no classification by ITMI), Clinvitae (3x, as benign, 1x, as uncertain significance by ClinVar), Insight Colon Cancer Gene Variant Database (5x, as class 3), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (6x, as class 3). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1281 of 277210 (8 homozygous) chromosomes at a frequency of 0.004621 in the following populations: African in 237 of 24026 chromosomes (freq. 0.010), other in 31 of 6466 chromosomes (freq. 0.005), Latino in 49 of 34420 chromosomes (freq. 0.0014), European in 488 of 126712 (4 homozygous) chromosomes (freq. 0.004), Ashkenazi Jewish in 76 of 10150 chromosomes (freq. 0.007), East Asian in 16 of 18866 chromosomes (freq. 0.0008), Finnish in 290 of 25794 chromosomes (freq. 0.011), and South Asian in 94 of 30776 (3 homozygous) chromosomes (freq. 0.003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic CHEK2 variant (c.1283C>T, p.Ser428Phe) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.His479Gln variant does not have clinical significance. The p.His479Gln residue is not conserved in mammals and the variant amino acid Glutamine (Gln) is present in Chimpanzees, increasing the likelihood that this variant does not have clinical significance, and 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.46
DANN	Benign	0.54
DEOGEN2	Benign	0.051	T;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.11	T;T;.;T;.
MetaRNN	Benign	0.0054	T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-1.1	N;.;.;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.63	N;N;.;.;.
REVEL	Benign	0.093
Sift	Benign	0.60	T;T;.;.;.
Sift4G	Benign	0.61	T;T;.;.;.
Polyphen		0.0	B;B;.;.;B
Vest4		0.055
MutPred		0.17		Gain of helix (P = 0.062);.;.;.;.;
MVP		0.26
MPC		0.036
ClinPred		0.000037	T
GERP RS		2.2
Varity_R		0.022
gMVP		0.17

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: rs63750685; hg19: chr7-6026959; COSMIC: COSV56225051;