7-5987275-C-T

Position:

chr7-5987275-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000535.7(PMS2):c.1490G>A(p.Gly497Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:4O:1

Conservation

PhyloP100: 2.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10595277).

BP6

Variant 7-5987275-C-T is Benign according to our data. Variant chr7-5987275-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127761.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Benign=1, Uncertain_significance=12}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.1490G>A	p.Gly497Asp	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 linkuse as main transcript	c.1490G>A	p.Gly497Asp	missense_variant	11/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251416

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000951

AC:

139

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000105

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 4

Uncertain:5

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 14, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 09, 2022	- -

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 21, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 10, 2015	- -

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 12, 2023	In the published literature, the variant has been reported in individuals with a variety of cancers including breast/ovarian (PMIDs: 33471991 (2021), 32809219 (2020), 31159747 (2019), 30651582 (2019), 30426508 (2018), 25186627 (2015)), endometrial (PMIDs: 31992580 (2020), 27443514 (2016)), pancreatic (PMID: 29945567 (2018)), and colorectal (PMIDs: 34250417 (2021), 28135145 (2017), 25559809 (2015)). It has also been reported in unaffected individuals (PMIDs: 33471991 (2021), 24728327 (2014)). The frequency of this variant in the general population, 0.00021 (27/129168 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 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	GeneDx	Dec 05, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including colorectal, endometrial, ovarian, and/or breast cancer (PMID: 25559809, 25186627, 27443514, 28135145, 30651582, 30426508, 32809219, 31992580, 34250417); This variant is associated with the following publications: (PMID: 28135145, 30502717, 31433215, 25559809, 24728327, 26689913, 27443514, 25186627, 22608206, 30651582, 31159747, 31391288, 31992580, 30426508, 32809219, 34250417, 29945567, 34284872) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 10, 2021	The PMS2 c.1490G>A; p.Gly497Asp variant (rs199739859) is reported in the literature in six probands who were affected with colorectal (3), endometrial (2), or ovarian (1) cancer as well as multiple affected relatives (Chubb 2015, Krivokuca 2019, Ring 2016, Wang 2020, and Yurgelun 2017). This variant is also reported in ClinVar (Variation ID: 127761) and is found in the general population with an allele frequency of 0.011% (32/282,816 alleles) in the Genome Aggregation Database. The glycine at codon 497 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.252). Due to limited information, the clinical significance of the p.Gly497Asp variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2023	Variant summary: PMS2 c.1490G>A (p.Gly497Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251416 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. BLAT search for the region surrounding the variant suggests no pseudogene interference in this region. c.1490G>A has been reported in the literature in individuals affected with various types of cancers including but not limited to rectal cancer, colorectal cancer, epithelial ovarian cancer, pancreatic cancer and hereditary breast and ovarian cancer (example: Chubb_2015, Ring_2016, Krivokuca_2019, Young_2018). These reports however, 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. 13 other ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=3) or uncertain significance (n=10). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PMS2 p.Gly497Asp variant was identified in 2 of 2014 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer or endometrial carcinoma (Chubb 2015, Ring 2016). The variant was also identified in the following databases: dbSNP (ID: rs199739859) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by GeneDx, Invitae, and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, Cosmic (1x in central nervous system), and Insight Hereditary Tumors database. The variant was not identified in the COGR, MutDB, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant databases. The variant was identified in control databases in 33 of 277164 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 2 of 6466 chromosomes (freq: 0.0003), Latino in 3 of 34420 chromosomes (freq: 0.0001), European in 27 of 126690 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10148 chromosomes (freq: 0.0001); but not in the African, East Asian, Finnish, and South Asian populations. The p.Gly497 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. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.099

T;.;.;.;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.61

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.61

T;T;.;T;.

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.4

L;.;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.79

N;N;.;.;.

REVEL

Benign

0.25

Sift

Benign

0.20

T;T;.;.;.

Sift4G

Benign

0.61

T;T;.;.;.

Polyphen

0.61

P;B;.;.;B

Vest4

0.19

MVP

0.50

MPC

0.043

ClinPred

0.063

GERP RS

3.1

Varity_R

0.036

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over