chr7-5987275-C-T

Variant names:

• chr7-5987275-C-T
• rs199739859
• NM_000535.7:c.1490G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:4 O:1
• Conservation: PhyloP100: 2.46

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 -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: {Uncertain_significance=13, Benign=1, Likely_benign=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1490G>A	p.Gly497Asp	missense_variant	Exon 11 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1490G>A	p.Gly497Asp	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152142 Hom.: 0 Cov.: 31

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: 29 AN: 251416 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135886

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.: 0 Cov.: 41 AF XY: 0.000100 AC XY: 73 AN XY: 727224

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: 11 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74312

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.: 0

Bravo AF: 0.0000642

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Oct 03, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.1490G>A (p.Gly497Asp) variant has been reported in the published literature in individuals with a variety of cancers including breast/ovarian (PMIDs: 34326862 (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 (PMID: 24728327 (2014)). It has also been found in breast cancer cases as well as in reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). 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. -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history including colorectal, endometrial, ovarian, and/or breast cancer, but also seen in unaffected controls (PMID: 25559809, 25186627, 27443514, 28135145, 30651582, 30426508, 32809219, 31992580, 34250417, 34326862, 33471991); In silico analysis indicates that this missense variant does not alter protein structure/function; 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, 33471991, 34326862) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Lynch syndrome 4 Uncertain:5

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 14, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:2

Nov 30, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 10, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 21, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Nov 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 breast and/or ovarian cancer (e.g. Chubb_2015, Ring_2016, Krivokuca_2019, Young_2018). 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: 25559809, 26689913, 27443514, 28135145, 29945567, 30651582, 30426508, 31159747, 31992580, 32809219, 34250417, 34326862). ClinVar contains an entry for this variant (Variation ID: 127761). Based on the evidence outlined above, the variant was classified as likely benign. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.40
DEOGEN2	Benign	0.099	T;.;.;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.61	T;T;.;T;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.4	L;.;.;.;.
PrimateAI	Benign	0.25	T
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	T
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

Other links and lift over

dbSNP: rs199739859; hg19: chr7-6026906; COSMIC: COSV56224927;