7-5977683-C-T

Variant names:

• chr7-5977683-C-T
• rs143340522
• NM_000535.7:c.2350G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000535.7(PMS2):​c.2350G>A​(p.Asp784Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000618 in 1,606,010 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (6 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (27 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:14
• Conservation: PhyloP100: 7.90

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0129443705).
• BP6: Variant 7-5977683-C-T is Benign according to our data. Variant chr7-5977683-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=2, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.002 (301/150268) while in subpopulation AFR AF= 0.00631 (258/40914). AF 95% confidence interval is 0.00567. There are 6 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2350G>A	p.Asp784Asn	missense_variant	Exon 14 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2350G>A	p.Asp784Asn	missense_variant	Exon 14 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 298 AN: 150166 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000728

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00529

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000445

Gnomad OTH AF: 0.00146

GnomAD3 exomes AF: 0.00114 AC: 285 AN: 250126 Hom.: 9 AF XY: 0.00115 AC XY: 156 AN XY: 135168

Gnomad AFR exome AF: 0.00685

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00505

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000475 AC: 691 AN: 1455742 Hom.: 27 Cov.: 32 AF XY: 0.000548 AC XY: 397 AN XY: 724190

Gnomad4 AFR exome AF: 0.00698

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00420

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.000848

GnomAD4 genome AF: 0.00200 AC: 301 AN: 150268 Hom.: 6 Cov.: 30 AF XY: 0.00184 AC XY: 135 AN XY: 73296

Gnomad4 AFR AF: 0.00631

Gnomad4 AMR AF: 0.000727

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00529

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000445

Gnomad4 OTH AF: 0.00145

Alfa AF: 0.0000490 Hom.: 0

ESP6500AA AF: 0.00615 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00140 AC: 170

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 4 Uncertain:1 Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jun 01, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -

Oct 15, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

.The PMS2 c.2350G>A variant is classified as Benign (BS2) -

not specified Benign:4

Jan 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 30, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change does not appear to have been previously described in patients with PMS2-related disorders. Due to high homology with other regions of the genome, the information regarding this sequence change in the population databases such as ExAC and gnomAD may not reliable. The p.Asp784Asn change affects a moderately conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp784Asn substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp784Asn change remains unknown at this time. -

Sep 28, 2020

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.2350G>A (p.Asp784Asn) results in a conservative amino acid change located in the C-terminal dimerization domain (IPR014790) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 280910 control chromosomes, predominantly within the African- and South Asian subpopulation (at a frequency of 0.0065 and 0.005, respectively) in the gnomAD database, including 11 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 90-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. The variant, c.2350G>A, has been reported in the literature in an individual with suspected Lynch Syndrome (e.g. Yurgelun_2015, Li_2020), and other individuals with breast- and/or ovarian cancer (e.g. Tung_2014, Chan_2018, da Costa 2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with another pathogenic PSM2 variant has been reported (PMS2 c.2186_2187delTC, p.Leu729fsX6; in our internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS 5x, likely benign 3x). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Apr 01, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 29, 2019

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. -

Jan 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 784 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 reported in individuals affected with Lynch syndrome (PMID: 25980754) and breast/ovarian cancer (PMID: 25186627, 32039725, 32959997). This variant has been identified in 278/244936 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable, because the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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 provided Uncertain:1 Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: BS2 -

Jun 26, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.2350G>A (p.Asp784Asn) variant has been reported in the published literature in individuals with ovarian cancer (PMID: 30093976 (2018)), suspected Lynch syndrome (PMID: 25980754 (2015)), and breast cancer (PMIDs: 25186627 (2015), 32039725 (2020), 32959997 (2020), and 33471991 (2021); LOVD (https://databases.lovd.nl/shared/)). In addition, this variant has been observed in reportedly healthy individuals (PMIDs: 31422574 (2019) and 33471991 (2021); LOVD (https://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.0065 (162/24750 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. However, frequency information may be unreliable in this region due to high homology with the PMS2 pseudogene PMS2CL. 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. -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.Asp784Asn variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs143340522) as “With Uncertain significance allele”, and in the ClinVar and Clinvitae databases (4x classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Counsyl). The variant was not identified in the following databases: COSMIC, MutDB, Insight Colon Cancer, Zhejiang Colon Cancer, Mismatch Repair or Insight Hereditary Tumors. The variant was identified in control databases in 278 of 244936 chromosomes at a frequency of 0.001 in the following populations: African in 106 of 15244 chromosomes (freq. 0.007, 4 homozygous); South Asian in 150 of 30678 chromosomes (freq. 0.005, 4 homozygous); population listed as “other” in 3 of 5468 chromosomes (freq. 0.0005, 1 homozygous); Latino in 9 of 33564 chromosomes (freq. 0.0003); East Asian in 2 of 17174 chromosomes (freq. 0.0001) and European non-Finnish in 8 of 110786 chromosomes (freq. 0.00007) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), however population data in this region of PMS2 are not considered reliable due to high pseudogene homology. The p.Asp784Asn residue is 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 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. The variant is located with the MutL, C-terminal, dimerisation functional domain. 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. -

Breast and/or ovarian cancer Benign:1

Apr 26, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PMS2-related disorder Benign:1

Jun 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;.;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;D;.;D
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.7	L;.;.;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;D;.;.;.;D
REVEL	Uncertain	0.35
Sift	Benign	0.077	T;D;.;.;.;D
Sift4G	Uncertain	0.013	D;D;.;.;.;T
Polyphen		0.98	D;D;.;.;D;D
Vest4		0.56
MVP		0.87
MPC		3.1
ClinPred		0.038	T
GERP RS		5.8
Varity_R		0.40
gMVP		0.46

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: rs143340522; hg19: chr7-6017314; COSMIC: COSV56221844;