chr7-5999199-T-G

Variant names:

• chr7-5999199-T-G
• rs587779342
• NM_000535.7:c.614A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP4 PP3 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000535.7: c.614A>C variant in PMS2 is a missense variant predicted to cause substitution of Glutamin by Prolin at amino acid 205 (p.Gln205Pro). This alteration was detected in trans with a mutation in PMS2 (c.1A>G) in an individual meeting the clinical criteria for CMMR-D (≥3 points, table 3 of the ClinGen_InSiGHTColorectalCancer/Polyposis_ACMG_Specifications_v1), (PM3 met). The Frequency of this variant in gnomAD V4.1.0 is 0.000037 (0.0037%), which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP threshold (<1 in 50,000 alleles) for PM2_supporting, and therefore PM2_supporting is not met. The variant was detected in at least one CRC/Endometrial MSI-H tumour using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). This missense variant mets the criteria for PP3 (MAPP+PolyPhen-2 prior probability for pathogenicity >0.68 & ≤0.81). Due to insufficient evidence, this variant is classified as a variant of uncertain significance for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM3, PP3, PP4 (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA012420/MONDO:0013699/139

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:5
• Conservation: PhyloP100: 7.58
• Publications: 14 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: Uncertain_significance. The variant received 4 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.614A>C	p.Gln205Pro	missense_variant	Exon 6 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.614A>C	p.Gln205Pro	missense_variant	Exon 6 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251496 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.0000454 AC XY: 33 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111966

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000215 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 4 Pathogenic:4 Uncertain:1

Nov 03, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous c.614A>C (p.Q205P) likely pathogenic variant in the PMS2 gene was detected in this individual. This variant has been previously described as disease-causing in mismatch repair cancer syndrome (PMID: 18602922, 25980754), an autosomal recessive cancer predisposition syndrome. In addition, functional studies have indicated that the p.Q205P change alters PMS2 enzymatic function (PMID: 24027009). Therefore, we consider this variant to be likely pathogenic. -

Jun 10, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18602922, 37296477; Myriad internal data]. -

Feb 08, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 04, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history of Lynch syndrome-associated tumors (PMID: 27435373, 34326862, 25980754); Published functional studies demonstrate repair efficiency significantly higher than that of a pathogenic control but compromised when compared to wild-type (PMID: 24027009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20531397, 19283792, 26247049, 18709565, 21376568, 26333163, 27435373, 31447099, 36240479, 34326862, 37296477, 25980754, 18602922, 11574484, Li_2024_Article, Plazzer2024[preprint], 37507074, 24027009, 38552658) -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 03, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in individuals suspected of Lynch syndrome (PMIDs: 27435373 (2016), 25980754 (2015)). Functional studies showed inconclusive results regarding the variant's impact on protein function (PMID: 24027009 (2013)). The frequency of this variant in the general population, 0.000008 (2/251496 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Pathogenic:3

May 01, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 10, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q205P variant (also known as c.614A>C), located in coding exon 6 of the PMS2 gene, results from an A to C substitution at nucleotide position 614. The glutamine at codon 205 is replaced by proline, an amino acid with similar properties. This alteration was detected in trans with a mutation in PMS2 (c.1A>G) in an individual diagnosed with colon cancer at 20 years, duodenal cancer at 41 years, and lymphoma (age at diagnosis was not provided). The proband had a family history of brain tumors diagnosed in two siblings in their 30s and immunohistochemistry demonstrated loss of PMS2 protein expression in both tumor and adjacent normal tissue (Senter L et al. Gastroenterology. 2008 Aug;135(2):419-28). This alteration was also identified once in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). In an in vitro study, this alteration displayed a decrease (~50%) in relative repair efficiency compared to wild type (100%), but was not classified as repair deficient because it had significantly higher repair levels than a known PMS2 mutation (Drost M et al. Hum. Mutat. 2013 Nov; 34(11):1477-80). Based on an internal structural assessment, this alteration may result in generalized destabilization of the ATPase domain near the MSH2/MSH6 binding interface (Guarn&eacute; A et al. EMBO J. 2001 Oct;20:5521-31; Groothuizen FS et al. Elife. 2015 Jul;4:e06744). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic, but may represent a reduced penetrance allele. -

Sep 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with proline at codon 205 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes partial reduction in DNA mismatch repair activity of PMS2 protein (PMID: 24027009). This variant has been reported in over ten individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; Clinvar SCV000285143.7, communication with an external laboratory). This variant has also been observed in multiple individuals who also carried the variant PMS2 c.1A>G (p.Met1?) and were affected with either early-onset colorectal cancers or uterine cancer (PMID: 18602922, 37296477). This variant has been identified in 2/251496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Likely Pathogenic. -

Lynch syndrome Pathogenic:2

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with proline at codon 205 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes partial reduction in DNA mismatch repair activity of PMS2 protein (PMID: 24027009). This variant has been reported in over ten individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; Clinvar SCV000285143.7, communication with an external laboratory). This variant has also been observed in compound heterozygous state with PMS2 c.1A>G (p.Met1?) in an individual affected with early-onset colon cancer, duodenal cancer, and lymphoma and a family history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). This variant has been identified in 2/251496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Likely Pathogenic. -

Aug 23, 2021

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.614A>C (p.Gln205Pro) variant in the PMS2 gene is located on the exon 6 and is predicted to replace glutamine with proline at codon 205 (p.Gln205Pro). This variant has also been observed in compound heterozygous state with PMS2 c.1A>G (p.Met1?) in an individual affected with early-onset colon cancer, duodenal cancer, and lymphoma and a family history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20531397). The variant has also been identified in 2 unrelated individuals with Lynch syndrome (PMID: 25980754, 27435373). Experimental study showed reduction in mismatch repair efficiency and negative functional impact of the variant (PMID: 24027009). The variant has been reported in ClinVar (ID: 91361). The variant is rare in the general population according to gnomAD (2/251496). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.823). Therefore, the c.614A>C (p.Gln205Pro) variant of PMS2 has been classified as likely pathogenic. -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 p.Gln205Pro variant was identified in 3 of 3510 proband chromosomes (frequency: 0.0009) from Dutch, American and multinational individuals or families with Lynch syndrome or suspected hereditary cancer (Yurgelun 2015, van der Klift 2016, Senter 2008). The variant was also identified in dbSNP (ID: rs587779342) as “With Uncertain significance” allele, ClinVar and Clinvitae (classified as uncertain significance, reviewed by an expert panel 2013; submitters: uncertain significance by InSIGHT, Ambry Genetics, Counsyl and GeneDx; and likely pathogenic by Invitae 2017), Insight Colon Cancer Gene Variant Database (3x), and Insight Hereditary Tumors Database (3x) and was not identified in Genesight-COGR, Cosmic, Zhejiang Colon Cancer Database, and Mismatch Repair Genes Variant Database. The variant was identified in control databases in 1 of 246270 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017), being identified in 1 of 111720 European Non-Finnish individuals (frequency: 0000009). Functional assays for splicing and mismatch repair deficiency demonstrated no allele specific imbalance however mismatch repair efficiency was reduced (van der Klift 2016, Drost 2013). In silico analysis using the bioinformatics tool PON-MMR2 that looks at evolutionary conservation and amino acid features, found the variant benign (Niroula 2015). Senter et al (2008) identified the variant as co-occurring with a pathogenic PMS2 variant (c.1A>G, 5’ truncation) in 1 individual diagnosed with CRC at 20 years old, who had 2 siblings with brain cancer. The variants are described as biallelic suggesting that the c.614A>C variant has clinical significance. The p.Gln205 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Pro variant may impact the protein; however, this information is not predictive enough to assume 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Sep 19, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.614A>C (p.Gln205Pro) results in a non-conservative amino acid change in 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 8e-06 in 251496 control chromosomes. c.614A>C has been reported in the literature in individuals affected Constitutional Mismatch Repair Deficiency and features of Lynch Syndrome (e.g. Senter_2008, Yurgelun_2015, Ercan_2024, Bhai_2021, Singh_2023). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect shows ~50% relative repair efficiency when compared to wild type (Drost_2013). The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 24027009, 38552658, 18602922, 37296477, 25980754). ClinVar contains an entry for this variant (Variation ID: 91361). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 205 of the PMS2 protein (p.Gln205Pro). This variant is present in population databases (rs587779342, gnomAD 0.0009%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency and clinical features of Lynch syndrome (PMID: 18602922, 25980754, 27435373). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 91361). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 2402700). For these reasons, this variant has been classified as Pathogenic. -

Breast and/or ovarian cancer Uncertain:1

Feb 09, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;M
PhyloP100		7.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.2	D;D;.;.;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.028	D;D;.;.;.;T
Sift4G	Uncertain	0.011	D;D;.;.;.;T
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.91
MutPred		0.64		Gain of catalytic residue at Q205 (P = 0.0604);.;.;.;.;Gain of catalytic residue at Q205 (P = 0.0604);
MVP		0.93
MPC		0.28
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.81
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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: rs587779342; hg19: chr7-6038830;