7-6002590-G-C

Variant names:

• chr7-6002590-G-C
• rs63750871
• NM_000535.7:c.400C>G
• PMS2 p.Arg134Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2PP3_Moderate

The NM_000535.7(PMS2):c.400C>G (p.Arg134Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R134P: Uncertain_significance (ClinVar VariationId 1737100, 1 star); p.R134Q: Uncertain_significance (ClinVar VariationId 423246, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.96
• Publications: 8 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: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 3 benign (OR vs. background: 3.6).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000336 by highest known P/LP ClinVar AF 0.000336) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

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>G p.Arg134Gly	missense	Exon 5 of 15	Prot: NP_000526.2 UniProt:
	PMS2 NM_001322009.2		c.-6C>G	5_prime_UTR_premature_start_codon_gain	Exon 5 of 15	Prot: NP_001308938.1 UniProt:
	PMS2 NM_001406887.1		c.-6C>G	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>Gp.Arg134Gly

Exon rankExon 5 of 15

missense

Prot: NP_000526.2UniProt: P54278-1

PMS2 NM_001322009.2

HGVSc / HGVSpc.-6C>G

Exon rankExon 5 of 15

5_prime_UTR_premature_start_codon_gain

Prot: NP_001308938.1UniProt: A0A8V8TQ92

PMS2 NM_001406887.1

HGVSc / HGVSpc.-6C>G

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>G p.Arg134Gly	missense	Exon 5 of 15	Prot: ENSP00000265849.7 UniProt:
	PMS2 ENST00000382321.5	TSL:1	c.400C>G p.Arg134Gly	missense	Exon 5 of 11	Prot: ENSP00000371758.4 UniProt:
	PMS2 ENST00000406569.8	TSL:1	n.400C>G	non_coding_transcript_exon	Exon 5 of 13	Prot: ENSP00000514464.1 UniProt:

PMS2 ENST00000265849.12

TSL:1MANE Select

HGVSc / HGVSpc.400C>Gp.Arg134Gly

Exon rankExon 5 of 15

missense

Prot: ENSP00000265849.7UniProt: P54278-1

PMS2 ENST00000382321.5

TSL:1

HGVSc / HGVSpc.400C>Gp.Arg134Gly

Exon rankExon 5 of 11

missense

Prot: ENSP00000371758.4UniProt: P54278-2

PMS2 ENST00000406569.8

TSL:1

HGVSc / HGVSpn.400C>G

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.76
GPN-Star LLR	N/A	-8.4
GPN-Star score	N/A	8.4
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	28/72	disease causing
MutationAssessor	Pathogenic	3.7	H
PhyloP100	Uncertain	6.0
popEVE	Benign	-3.9
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0070	D
Varity_R	N/A	0.82
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
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: rs63750871;

hg19: chr7-6042221;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar