7-5982885-C-T

Variant names:

• chr7-5982885-C-T
• rs267608161
• NM_000535.7:c.2113G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000535.7(PMS2):​c.2113G>A​(p.Glu705Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,604,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000266218: In addition, this variant has been shown to affect mismatch repair in yeast models (Erdeniz 2007, Deschenes 2007)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E705D) has been classified as Likely pathogenic. The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 U:1
• Conservation: PhyloP100: 7.90
• Publications: 29 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: Orphanet, ClinGen
• Lynch syndrome 4

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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

Specifications for PMS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000266218: In addition, this variant has been shown to affect mismatch repair in yeast models (Erdeniz 2007, Deschenes 2007).; SCV004847564: "In vitro functional studies provide some evidence that this variant impacts protein function (Martinez 2010, Drost 2013)"; SCV000149583: Published functional studies demonstrate a damaging effect: defective homologous recombination and mismatch repair activities (Kadyrov et al., 2006; Erdeniz et al., 2007; Deschenes et al., 2007; Martinez et al., 2010; van Oers et al., 2010; Drost et al., 2013); SCV004218975: Functional studies have shown that this variant causes defective DNA mismatch repair (PMIDs: 16873062 (2006), 17029773 (2007), 17567544 (2007), 20176959 (2010), 24027009 (2013), 33453991 (2020), 33510387 (2021), 35189042 (2022)).; SCV000274276: "In a functional study, the p.E705K variant inhibited mismatch repair activity in mammalian or yeast cells when it was expressed in excess amounts relative to the wild-type PMS2. However, it did not affect protein stability or its interaction with MLH1, suggesting that the p.E705K variant may behave in a recessive manner (Deschenes SM et al. Cancer Lett. 2007;249(2):148-56). In another functional study, analysis of this alteration in mice showed an increase in genomic mutation frequency and tumor incidence (van Oers JM et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Jul; 107(30):13384-9). In addition, this variant has been identified to have deficient function in several other assays (Ortega J et al. Cell Res, 2021 May;31:542-553; D'Arcy BM et al. Mol Genet Genomic Med, 2022 Feb;10:e1908)."; SCV004359549: It has also been shown to result in loss of PMS2 function in an endonuclease assay, a 6-thioguanine sensitivity assay and a mutator phenotype assay (PMID: 16873062, 17029773, 17567544).; SCV006324637: MMR assays have shown that the variant completely suppresses MMR activity (odds of pathogenicity = 32.93; PMID: 24027009; 17029773; 35189042) (PS3).; SCV000551983: Experimental studies have shown that this missense change affects PMS2 function (PMID: 16873062, 17029773, 17567544, 20176959, 20624957, 24027009).; SCV002598654: The most pronounced variant effect results in 10%-<30% of normal activity (Martinez_2010, Drost_2013).; SCV004187581: Functional studies indicate this variant impacts protein function [PMID: 16873062, 20624957].; SCV005366606: Functional studies showed that this variant significantly affects homologous recombination and inhibits mismatch repair activities (Kadyrov et al. 2006. PubMed ID: 16873062; Martinez et al. 2010. PubMed ID: 20176959; Drost et al. 2013. PubMed ID: 24027009).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 49 uncertain in NM_000535.7
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-5982883-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 573081.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 7-5982885-C-T is Pathogenic according to our data. Variant chr7-5982885-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 91328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.2113G>A	p.Glu705Lys	missense	Exon 12 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.2299G>A	p.Glu767Lys	missense	Exon 13 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.2113G>A	p.Glu705Lys	missense	Exon 12 of 15	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2113G>A	p.Glu705Lys	missense	Exon 12 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.910G>A	p.Glu304Lys	missense	Exon 8 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000469652.1	TSL:1	n.83G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151518 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000487

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: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 9 AN: 226056 AF XY: 0.0000325

Gnomad AFR exome AF: 0.0000768

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: 0.0000803

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 21 AN: 1452922 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 722454

African (AFR) AF: 0.0000302 AC: 1 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 43828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4400

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1107354

Other (OTH) AF: 0.0000334 AC: 2 AN: 59928

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151518 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3 AN XY: 73980

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

African (AFR) AF: 0.0000487 AC: 2 AN: 41068

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0188335), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000743 AC: 9

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
4	-	-	Hereditary cancer-predisposing syndrome (4)
3	-	-	Lynch syndrome 4 (3)
2	-	-	Lynch syndrome (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome 1 (1)
1	-	-	Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 (1)
1	-	-	PMS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.95
MPC		3.5
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267608161; hg19: chr7-6022516;