7-6002515-C-T

Position:

chr7-6002515-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001322011.2(PMS2):c.-410G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000664 in 1,611,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

PMS2
NM_001322011.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:3

Conservation

PhyloP100: 1.39

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 -1 ACMG points.

BP6

Variant 7-6002515-C-T is Benign according to our data. Variant chr7-6002515-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127791.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.475G>A	p.Val159Met	missense_variant	5/15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.475G>A	p.Val159Met	missense_variant	5/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250682

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135566

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1459422

Hom.:

Cov.:

AF XY:

0.0000620

AC XY:

AN XY:

726052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000810

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 30, 2024	The PMS2 c.475G>A (p.Val159Met) variant has been reported in the published literature in individuals affected with colorectal cancer (PMIDs: 28466842 (2017), 25559809 (2015)), stomach adenocarcinoma (PMIDs: 26689913 (2015)), and breast cancer (PMIDs: 32658311 (2021), 31465090 (2019), 26689913 (2015)). In a large breast cancer association study, the variant was reported in both cases and controls (PMID: 33471991 (2021), see also LOVD https://databases.lovd.nl/shared/variants/PMS2). The frequency of this variant in the general population, 0.00012 (16/128726 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 conflicting predictions that this variant is benign or damaging. 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	Jan 23, 2024	Observed in individuals with a personal and/or family history of colorectal, breast, prostate, or stomach cancer (PMID: 25559809, 26689913, 28466842, 29684080, 31465090, 32658311, 32832836); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25559809, 26689913, 28466842, 29684080, 28873162, 29354287, 31391288, 31465090, 32832836, 32658311, 11574484) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2022	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	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2023	This missense variant replaces valine with methionine at codon 159 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal cancer (PMID: 25559809), stomach adenocarcinoma (PMID: 26689913), and breast cancer (PMID: 26689913, 29684080, 31465090). This variant has been identified in 17/245638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 03, 2024	Variant summary: PMS2 c.475G>A (p.Val159Met) results in a conservative amino acid change located in the Histidine kinase/HSP90-like ATPase (IPR003594) 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 6.4e-05 in 250682 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (6.4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.475G>A has been reported in the literature in individuals affected with various tumor phenotypes (Lu 2015, Chubb 2015, ALcay_2021, Stuttgen_2019, Boujemaa_2024, Wang_2019). These report(s) 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: 32658311, 38313678, 25559809, 28466842, 26689913, 31465090). ClinVar contains an entry for this variant (Variation ID: 127791). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Lynch syndrome 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Feb 20, 2023	ACMG criteria used to clasify this variant:PS4_MOD, PM2_SUP, PP3 -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PMS2 p.Val159Met variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was identified in dbSNP (ID: rs142416537) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (as uncertain significance by GeneDx, Invitae and Ambry Genetics), Clinvitae (4x), Insight Hereditary Tumors Database (1x), and in control databases in 17 of 245638 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 16 of 111290 chromosomes (freq: 0.0001), European Finnish in 1 of 22242 chromosomes (freq: 0.00005), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Val159 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Met 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. -

PMS2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

The PMS2 c.475G>A variant is predicted to result in the amino acid substitution p.Val159Met. This variant was reported as a variant of uncertain significance in an individual with breast cancer (Stuttgen et al. 2019. PubMed ID: 31465090) and was also reported in cohorts of individuals with colorectal cancer (Chubb et al. 2015. PubMed ID: 25559809, Table A1; Haraldsdottir et al. 2017. PubMed ID: 28466842). Additionally, this variant was reported in an individual with stomach adenocarcinoma (Lu et al. 2015. PubMed ID: 26689913, supplementary table 12) and in a cohort of individuals with cancer (Yehia et al. 2018. PubMed ID: 29684080, Table S9). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In the ClinVar database, this variant has been listed as 'uncertain' or 'likely benign' by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/127791/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

This missense variant replaces valine with methionine at codon 159 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with colorectal cancer (PMID: 25559809), stomach adenocarcinoma (PMID: 26689913), and breast cancer (PMID: 26689913, 29684080, 31465090). This variant has been identified in 17/245638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 10, 2024

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2025

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Sep 11, 2024

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;.;.;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.024

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.86

D;D;.;D;.;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.44

T;T;T;T;T;T

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.4

M;.;.;.;.;M

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

N;N;.;.;.;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.0060

D;D;.;.;.;D

Sift4G

Uncertain

0.016

D;D;.;.;.;D

Polyphen

1.0

D;D;.;.;D;D

Vest4

0.64

MVP

0.82

MPC

0.22

ClinPred

0.75

GERP RS

4.5

Varity_R

0.16

gMVP

0.53

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