NM_000535.7:c.137G>T

Variant names:

• chr7-6005918-C-A
• rs121434629
• NM_000535.7:c.137G>T
• PMS2 p.Ser46Ile

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 19 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPM5PP3_StrongPP5_Very_Strong

The NM_000535.7(PMS2):c.137G>T (p.Ser46Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000282 (AC=454) in the gnomAD database across 1,610,770 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000328. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.54). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000469744: Borras et al. (2013) demonstrated through in vitro expressions studies that the p.Ser46Ile variant had significantly reduced mismatch repair activity, approximately 13% that of wild type, while Drost et al. (2013) showed that the p.Ser46Ile variant had a mismatch repair efficiency similar to that of a known pathogenic variant." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.S46N: Pathogenic/Likely_pathogenic (ClinVar VariationId 91301, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S46G: Uncertain_significance (ClinVar VariationId 525851, 1 star); p.S46R: Uncertain_significance (ClinVar VariationId 1771527, 1 star); p.S46= (synonymous): Likely_benign (ClinVar VariationId 1771525, 1 star) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:54 O:1
• Conservation: PhyloP100: 7.54
• Publications: 92 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: Labcorp Genetics (formerly Invitae), G2P, 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: Labcorp Genetics (formerly Invitae), G2P
• 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

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 19 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000469744: Borras et al. (2013) demonstrated through in vitro expressions studies that the p.Ser46Ile variant had significantly reduced mismatch repair activity, approximately 13% that of wild type, while Drost et al. (2013) showed that the p.Ser46Ile variant had a mismatch repair efficiency similar to that of a known pathogenic variant.; SCV000840051: "In addition, functional studies have shown that the c.137G>T (p.S46I) variant significantly impairs mismatch repair activity (PMID: 23709753, 24027009)."; SCV004019868: Functional studies indicate this variant impacts protein function [PMID: 24027009, 23709753, 27435373, 30608896, 17557300].; SCV004031230: "functional studies support that the variant impairs mismatch repair activity (PMID: 23709753)."; SCV000108292: deficient protein function inferred from 2 independent assays; SCV000271259: In vitro functional studies provide some evidence that the p.Ser46Ile variant may impact protein function (Borras 2013 PMID:23709753, Drost 2013 PMID:24027009, Nakagawa 2004 PMID:15256438).; SCV000918033: Functional studies have shown the variant to cause deficient MMR activity (Borras 2013, Drost 2013, van der Klift 2016).; SCV004842155: Experimental studies showed this variant resulted in impaired mismatch repair activity and negative functional impact on the protein (PMID: 23709753, 24027009).; SCV000686122: Functional studies have shown that this variant significantly impairs the mismatch repair activity of PMS2 protein (PMID: 23709753, 24027009).; SCV006306110: "Functional assays at the protein level demostrated abrogated MMR function, proficient expression and nuclear localization (PMID: 23709753, 24027009) (PS3)."; SCV000149566: Published functional studies demonstrate a damaging effect: in vitro cell-free complementation assays showed deficient mismatch repair activity as well as reduced PMS2 expression (Nakagawa 2004, Borras 2013, Drost 2013).; SCV000601815: "In addition, experimental studies have shown this variant causes significantly reduced DNA mismatch repair activity in vitro (PMIDs: 30608896 (2019), 24027009 (2013), 23709753 (2013))."; SCV000604885: "both the p.Ser46Ile and p.Ser46Asn variants exhibit less than 10% of wild-type activity in mismatch repair in vitro assays" (Borras 2013, Drost 2013).; SCV002072174: "In vitro functional assays demonstrate decreased mismatch repair activity for the Ser46Ile variant compared to wild type." PMID:23709753; SCV004223967: PS3; SCV000253845: Experimental studies have shown that this missense change affects PMS2 function (PMID: 23709753, 24027009).; SCV000592923: Functional assays have shown that this variant had reduced mismatch repair efficiency (Drost 2013) and resulted in near absence of the PMS2 protein (Auclair 2007).; SCV004046408: "In vitro experimental studies have shown that this variant impairs the mismatch repair activity of PMS2." PMID:23709753, PMID:24027009; SCV005045097: Functional studies show deficient mismatch repair activity, indicating that this variant impacts protein function (Borras E et al., PMID: 23709753; Drost M et al., PMID: 24027009; van der Klift HM et al., PMID: 27435373).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000328 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000336 by highest known P/LP ClinVar AF 0.000336) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.S46N: Pathogenic/Likely_pathogenic (ClinVar VariationId 91301, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.S46G: Uncertain_significance (ClinVar VariationId 525851, 1 star); p.S46R: Uncertain_significance (ClinVar VariationId 1771527, 1 star); p.S46= (synonymous): Likely_benign (ClinVar VariationId 1771525, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (54/54 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMS2 NM_000535.7	MANE Select	c.137G>T p.Ser46Ile	missense	Exon 2 of 15	Prot: NP_000526.2 UniProt:
	PMS2 NM_001406866.1		c.323G>T p.Ser108Ile	missense	Exon 3 of 16	Prot: NP_001393795.1 UniProt:
	PMS2 NM_001322014.2		c.137G>T p.Ser46Ile	missense	Exon 2 of 15	Prot: NP_001308943.1 UniProt:

PMS2 NM_000535.7

MANE Select

HGVSc / HGVSpc.137G>Tp.Ser46Ile

Exon rankExon 2 of 15

missense

Prot: NP_000526.2UniProt: P54278-1

PMS2 NM_001406866.1

HGVSc / HGVSpc.323G>Tp.Ser108Ile

Exon rankExon 3 of 16

missense

Prot: NP_001393795.1UniProt: A0A8V8TNX6

PMS2 NM_001322014.2

HGVSc / HGVSpc.137G>Tp.Ser46Ile

Exon rankExon 2 of 15

missense

Prot: NP_001308943.1UniProt: A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMS2 ENST00000265849.12	TSL:1MANE Select	c.137G>T p.Ser46Ile	missense	Exon 2 of 15	Prot: ENSP00000265849.7 UniProt:
	PMS2 ENST00000382321.5	TSL:1	c.137G>T p.Ser46Ile	missense	Exon 2 of 11	Prot: ENSP00000371758.4 UniProt:
	PMS2 ENST00000406569.8	TSL:1	n.137G>T	non_coding_transcript_exon	Exon 2 of 13	Prot: ENSP00000514464.1 UniProt:

PMS2 ENST00000265849.12

TSL:1MANE Select

HGVSc / HGVSpc.137G>Tp.Ser46Ile

Exon rankExon 2 of 15

missense

Prot: ENSP00000265849.7UniProt: P54278-1

PMS2 ENST00000382321.5

TSL:1

HGVSc / HGVSpc.137G>Tp.Ser46Ile

Exon rankExon 2 of 11

missense

Prot: ENSP00000371758.4UniProt: P54278-2

PMS2 ENST00000406569.8

TSL:1

HGVSc / HGVSpn.137G>T

Exon rankExon 2 of 13

non_coding_transcript_exon

Prot: ENSP00000514464.1UniProt: P54278-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000164	AC:25	Hom:0	AN:152222	Cov:33
GnomAD2 exomes	AF: 0.000163	AC:40	Hom:	AN:245780	Cov:
GnomAD4 exome	AF: 0.000294	AC:429	Hom:0	AN:1458548	Cov:31
GnomAD4 genome	AF: 0.000164	AC:25	Hom:0	AN:152222	Cov:33
TOPMed (Bravo)	AF: 0.000128	AC:34	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000207	AC:23	Hom:0	AN:111130	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000135	AC:1	Hom:	AN:7406	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000387	11	28420	0.000312	9	28844
Epi25(Epilepsy)	0.000143	6	41958	0.000269	18	66886
SCHEMA(Schizophrenia)	0.000363	44	121284	0.000491	93	189434

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
17	-	-	not provided (17)
12	-	-	Lynch syndrome 4 (12)
5	-	-	Hereditary cancer-predisposing syndrome (5)
5	-	-	Lynch syndrome (5)
4	-	-	Inherited MMR deficiency (Lynch syndrome) (4)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9 (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome 1 (2)
1	-	-	Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 (1)
1	-	-	Mismatch repair cancer syndrome 1 (1)
1	-	-	Mismatch repair cancer syndrome 4 (1)
1	-	-	Pituitary carcinoma (1)
1	-	-	PMS2-related cancer disorders (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-8.4
GPN-Star score	N/A	8.4
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.89	D
Mutation Taster	N/A	3/97	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.3	H
PhyloP100	Pathogenic	7.5
popEVE	Benign	-4.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.99
VESM-3B	Benign	-15

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121434629;

hg19: chr7-6045549;

COSMIC: COSV56151410;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar