7-5987522-C-T

Position:

chr7-5987522-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000535.7(PMS2):c.1243G>A(p.Val415Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,614,136 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). Synonymous variant affecting the same amino acid position (i.e. V415V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:10O:1

Conservation

PhyloP100: 0.453

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04859841).

BP6

Variant 7-5987522-C-T is Benign according to our data. Variant chr7-5987522-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142561.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, not_provided=1, Benign=2, Uncertain_significance=4}. Variant chr7-5987522-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 linkuse as main transcript	c.1243G>A	p.Val415Met	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.1243G>A	p.Val415Met	missense_variant	11/15	1	NM_000535.7	ENSP00000265849	P3	P54278-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251130

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000162

AC:

237

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000189

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000190

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history of breast, ovarian, pancreatic, or other cancer (Lu 2015, Zhang 2015, Hu 2016, Yadav 2016, Cock-Rada 2017); This variant is associated with the following publications: (PMID: 22941189, 27846281, 26689913, 26483394, 26580448, 27878467, 28528518, 31433215, 31391288, 31422574, 31327751, 25567908) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PMS2: BP4, BS1:Supporting -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2022	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 29, 2019	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 05, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2016	- -

Lynch syndrome 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 30, 2022	The PMS2 c.1243G>A (p.Val415Met) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with colorectal cancer and/or Lynch syndrome (PMID: 31433215). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2023	Variant summary: PMS2 c.1243G>A (p.Val415Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. However, the variant is located in a region that 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.1243G>A has been reported in the literature in sequencing studies of individuals affected with cancer including pancreatic cancer, acute megakaryoblastic leukemia, breast and/or ovarian cancer and colon cancer (e.g. Hu_2022, Guindalini_2022, Cock-Rada 2018, Hu 2016, Lu_2015, Okkels_2019, Yadav 2017, Zhang 2015). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 26689913, 25567908, 27878467, 28528518, 26580448, 31422574, 31433215). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=5; likely benign, n=4; Benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

PMS2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2024

The PMS2 c.1243G>A variant is predicted to result in the amino acid substitution p.Val415Met. This variant has been reported in an individual with lung adenocarcinoma (Drilon et al. 2015. PubMed ID: 25567908), pediatric acute megakaryoblastic leukemia (Zhang et al. 2015. PubMed ID: 26580448), metastatic prostate cancer (Zhu et al. 2019. PubMed ID: 31327751), personal or family history of breast/ovarian cancer (Yadav et al. 2017. PubMed ID: 27878467; Cock-Rada et al. 2018. PubMed ID: 28528518; Table S12, Lu et al. 2015. PubMed ID: 26689913) and as a germline variant in a patient with Lynch syndrome (Okkels at al. 2019. PubMed ID: 31433215). This variant was also observed as germline variant in patient with unspecified cancer with microsatellite instability and was assessed as likely benign by authors (Supplement 1, Li et al. 2020. PubMed ID: 31391288). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142561/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

in vivo

Oncological Genetic Counseling Clinic, "Carlo Poma" Hospital

Aug 16, 2022

- -

Endometrial carcinoma

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PMS2 p.Val415Met variant was identified in 3 of 456 proband chromosomes (frequency: 0.007) from individuals or families with lung adenocarcinoma, breast, ovarian or pancreatic cancer (Cock-Rada 2018, Drilon 2016, Hu 2016). The variant was also identified in dbSNP (ID: rs138387687 as "With Uncertain significance allele"), ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America), and Cosmic (3x in lung, stomach or salivary gland). The variant was not identified in GeneInsight-COGR, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 44 of 277090 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24008 chromosomes (freq: 0.00004), Latino in 10 of 34418 chromosomes (freq: 0.0003), European in 32 of 126634 chromosomes (freq: 0.0003), and Finnish in 1 of 25792 chromosomes (freq: 0.00004), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Val415 residue is not conserved in mammals and 4 of 5 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 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 colon cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Likely benign and reported on 06-15-2020 by 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

0.093

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.7

DANN

Benign

0.95

DEOGEN2

Benign

0.095

T;.;.;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.68

T;T;.;T;.

M_CAP

Benign

0.024

MetaRNN

Benign

0.049

T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.1

L;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.46

N;N;.;.;.

REVEL

Benign

0.18

Sift

Benign

0.091

T;T;.;.;.

Sift4G

Benign

0.23

T;T;.;.;.

Polyphen

0.59

P;P;.;.;P

Vest4

0.094

MVP

0.40

MPC

0.037

ClinPred

0.046

GERP RS

1.6

Varity_R

0.030

gMVP

0.24

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