chr7-5978689-T-C

Variant names:

• chr7-5978689-T-C
• rs141893001
• NM_000535.7:c.2182A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000535.7(PMS2):​c.2182A>G​(p.Thr728Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T728I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0078 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (33 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 1.57
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010939866).
• BP6: Variant 7-5978689-T-C is Benign according to our data. Variant chr7-5978689-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192223.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.2182A>G	p.Thr728Ala	missense	Exon 13 of 15	NP_000526.2
	PMS2	NM_001406866.1		c.2368A>G	p.Thr790Ala	missense	Exon 14 of 16	NP_001393795.1
	PMS2	NM_001322014.2		c.2182A>G	p.Thr728Ala	missense	Exon 13 of 15	NP_001308943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2182A>G	p.Thr728Ala	missense	Exon 13 of 15	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.979A>G	p.Thr327Ala	missense	Exon 9 of 11	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.1679-975A>G		intron	N/A	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1150 AN: 148006 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00333

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00344

GnomAD2 exomes AF: 0.00203 AC: 467 AN: 229692 AF XY: 0.00152

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.000312

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000189

Gnomad OTH exome AF: 0.00244

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00102 AC: 1460 AN: 1434356 Hom.: 33 Cov.: 30 AF XY: 0.000907 AC XY: 648 AN XY: 714224

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0348 AC: 1101 AN: 31646

American (AMR) AF: 0.00218 AC: 97 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.000270 AC: 7 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.0000586 AC: 5 AN: 85300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52736

Middle Eastern (MID) AF: 0.00298 AC: 17 AN: 5698

European-Non Finnish (NFE) AF: 0.000116 AC: 126 AN: 1090044

Other (OTH) AF: 0.00181 AC: 107 AN: 59272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00781 AC: 1156 AN: 148104 Hom.: 16 Cov.: 32 AF XY: 0.00737 AC XY: 533 AN XY: 72350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0282 AC: 1088 AN: 38522

American (AMR) AF: 0.00332 AC: 50 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10420

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67526

Other (OTH) AF: 0.00341 AC: 7 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00543 Hom.: 1

ExAC AF: 0.00379 AC: 456

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Jul 27, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 12, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.2182A>G (p.Thr728Ala) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 229692 control chromosomes, predominantly at a frequency of 0.029 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 408.31 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 African or African-American origin. c.2182A>G has been reported in the literature in individuals. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

Hereditary cancer-predisposing syndrome Benign:3

Aug 20, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr728Ala variant is not predicted to disrupt the existing acceptor splice site 8bp upstream by any splice site algorithm. The p.Thr728Ala variant is not predicted to introduce a novel splice site by any splice site algorithm. The p.Thr728Ala missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The alanine residue at codon 728 of PMS2 is present in Lesser Egyptian jerboa and 2 other mammalian species. The nucleotide c.2182 in PMS2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign.

Nov 17, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

May 05, 2025

Spanish MMR Variant Interpretation Working Group

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 variant c.2182A>G replaces threonine with alanine at codon 728 of the protein, p.(Thr728Ala). The threonine residue is weakly conserved, and there is a small physicochemical difference between threonine and alanine. It has a Maximum Credible Allele Frequency (MCAF) above 0.28% in the gnomAD v4.1.0 database (BA1; the allele frequency data may be inaccurate due to possible PMS2CL pseudogene interference). The SpliceAI algorithm predicts no significant impact on splicing. It is a missense variant with a MAPP+PolyPhen-2 prior probability of pathogenicity of <0.11 (BP4). There are no other described class 4/5 variants located at the same residue. To our current knowledge, no functional assays have been reported for this variant. It has been reported in our Spanish cohort in a patient affected by CRC showing MSS and conserved MMR protein expression. Based on the available evidence, this variant is classified as Benign (Class 1).

Lynch syndrome 1 Uncertain:1

Oct 30, 2014

Pathway Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breast and/or ovarian cancer Benign:1

Jun 18, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lynch syndrome Benign:1

May 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2 NM_000535.5:c.2182A>G has a 2.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Thr728Ala variant was identified in 1 of 192 proband chromosomes (frequency: 0.005) from individuals with pancreatic cancer (Hu 2016). The variant was identified in dbSNP (rs141893001) as “with uncertain significance allele” and ClinVar (classified as benign by Invitae, Ambry Genetics and VU University, likely benign by The Children's Hospital of Philadelphia and the University of Washington and uncertain significance by Integrated Genetics and Pathway Genomics). The variant was identified in control databases in 668 of 260,078 chromosomes (5 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 582 of 21,634 chromosomes (freq: 0.03), Other in 16 of 6782 chromosomes (freq: 0.002), Latino in 46 of 34,228 chromosomes (freq: 0.001), Ashkenazi Jewish in 3 of 9896 chromosomes (freq: 0.0003), European in 20 of 115,888 chromosomes (freq: 0.0002), South Asian in 1 of 28,826 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian, and Finnish populations. The p.Thr728Ala residue is not conserved in mammals and four out of five 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.51	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.21
MVP		0.79
MPC		1.8
ClinPred		0.0080	T
GERP RS		3.3
Varity_R		0.073
gMVP		0.32
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141893001; hg19: chr7-6018320; COSMIC: COSV99063705; COSMIC: COSV99063705;