rs63750871

Variant names:

• chr7-6002590-G-A
• rs63750871
• NM_000535.7:c.400C>T
• PMS2 p.Arg134*

Your query was ambiguous. Multiple possible variants found:

• chr7-6002590-G-A
• chr7-6002590-G-C

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 21 classification points (ACMG Germline Pathogenicity v2019). PVS1PS3PM2_SupportingPP5_Very_Strong

The NM_000535.7(PMS2):c.400C>T (p.Arg134*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.00000496 (AC=8) in the gnomAD database across 1,611,750 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000655. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000713220: "In vitro functional studies support an impact on protein function" (Parsons 1995 PMID:7632227, Nicolaides 1998 PMID:9488480, Gibson 2006 PMID:16426742)." and additional evidence is available in ClinVar. 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:24
• Conservation: PhyloP100: 5.96
• Publications: 2 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 21 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 5 of 15) at amino acid 134 of 862, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000713220: "In vitro functional studies support an impact on protein function" (Parsons 1995 PMID: 7632227, Nicolaides 1998 PMID: 9488480, Gibson 2006 PMID: 16426742).; SCV000918060: this variant was found to have a dominant negative effect in hamster fibroblast cells (Nicolaides_1998) but not in human fibroblast cells (Yamada_2003). However, the variant was found to abrogate the interaction with MLH1 (Nicolaides_1998), a known pathogenic mechanism.; SCV000889627: Functional studies indicate this variant causes impaired DNA mismatch repair activity (PMIDs: 9488480 (1998), 7632227 (1995)).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000655 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000336 by highest known P/LP ClinVar AF 0.000336) — PM2 supporting.
	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 (24/24 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.400C>T p.Arg134*	stop_gained	Exon 5 of 15	Prot: NP_000526.2 UniProt:
	PMS2 NM_001322009.2		c.-6C>T	5_prime_UTR_premature_start_codon_gain	Exon 5 of 15	Prot: NP_001308938.1 UniProt:
	PMS2 NM_001406887.1		c.-6C>T	5_prime_UTR_premature_start_codon_gain	Exon 5 of 15	Prot: NP_001393816.1 UniProt:

PMS2 NM_000535.7

MANE Select

HGVSc / HGVSpc.400C>Tp.Arg134*

Exon rankExon 5 of 15

stop_gained

Prot: NP_000526.2UniProt: P54278-1

PMS2 NM_001322009.2

HGVSc / HGVSpc.-6C>T

Exon rankExon 5 of 15

5_prime_UTR_premature_start_codon_gain

Prot: NP_001308938.1UniProt: A0A8V8TQ92

PMS2 NM_001406887.1

HGVSc / HGVSpc.-6C>T

Exon rankExon 5 of 15

5_prime_UTR_premature_start_codon_gain

Prot: NP_001393816.1UniProt: A0A8V8TQ92

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMS2 ENST00000265849.12	TSL:1MANE Select	c.400C>T p.Arg134*	stop_gained	Exon 5 of 15	Prot: ENSP00000265849.7 UniProt:
	PMS2 ENST00000382321.5	TSL:1	c.400C>T p.Arg134*	stop_gained	Exon 5 of 11	Prot: ENSP00000371758.4 UniProt:
	PMS2 ENST00000406569.8	TSL:1	n.400C>T	non_coding_transcript_exon	Exon 5 of 13	Prot: ENSP00000514464.1 UniProt:

PMS2 ENST00000265849.12

TSL:1MANE Select

HGVSc / HGVSpc.400C>Tp.Arg134*

Exon rankExon 5 of 15

stop_gained

Prot: ENSP00000265849.7UniProt: P54278-1

PMS2 ENST00000382321.5

TSL:1

HGVSc / HGVSpc.400C>Tp.Arg134*

Exon rankExon 5 of 11

stop_gained

Prot: ENSP00000371758.4UniProt: P54278-2

PMS2 ENST00000406569.8

TSL:1

HGVSc / HGVSpn.400C>T

Exon rankExon 5 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: 0.0000131	AC:2	Hom:0	AN:152178	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251140	Cov:
GnomAD4 exome	AF: 0.00000411	AC:6	Hom:0	AN:1459572	Cov:31
GnomAD4 genome Warning	AF: 0.0000131	AC:2	Hom:0	AN:152178	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000489	AC:1	Hom:0	AN:204374	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122560	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66884
SCHEMA(Schizophrenia)	0.00000969	1	103246	0.00000542	1	184486

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

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Lynch syndrome 4 (6)
5	-	-	not provided (5)
4	-	-	Lynch syndrome (4)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	Gastric 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	-	-	Mismatch repair cancer syndrome 1 (1)
1	-	-	Mismatch repair cancer syndrome 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	37
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
GPN-Star LLR	N/A	-8.7
GPN-Star score	N/A	8.7
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Uncertain	6.0

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.19
Pangolin loss	Benign	0.19	Position offset: 46
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 3 of 3 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: rs63750871;

hg19: chr7-6042221;

COSMIC: COSV99764106;

COSMIC: COSV99764106;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar