NM_000535.7:c.319C>T

Variant names:

• chr7-6003724-G-A
• rs188006077
• NM_000535.7:c.319C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_000535.7(PMS2):​c.319C>T​(p.Arg107Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000813 in 1,598,850 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: "SCV000187425: "In an in vitro mismatch repair (MMR) complementation assay, the MMR activity of p.R107W was reduced to less than 20% compared to wild type (100%), which was similar to other pathogenic/likely pathogenic variants in the assay (van der Klift HM et al. Hum. Mutat. 2016 11" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107L) has been classified as Uncertain significance. The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.84
• Publications: 15 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000187425: "In an in vitro mismatch repair (MMR) complementation assay, the MMR activity of p.R107W was reduced to less than 20% compared to wild type (100%), which was similar to other pathogenic/likely pathogenic variants in the assay (van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179)."; SCV000686190: Functional studies have shown that this variant causes a significant decrease in mismatch repair activity, with less than 20% of wild type protein activity (PMID: 27435373).; SCV000552039: Experimental studies have shown that this missense change affects PMS2 function (PMID: 27435373).; SCV004219001: Functional assays have shown this variant causes aberrant splicing and deficient mismatch repair activity (PMIDs: 26247049 (2015), 27435373 (2016)).; SCV000806214: Functional studies have demonstrated that this missense change affects PMS2 function wherein the mismatch repair activity was reduced to less than 20% compared to wild type (van der Klift et al. 2016. PubMed ID: 27435373).; SCV005429662: Functional studies have shown that this variant causes a significant decrease in mismatch repair activity, with less than 20% of wild type protein activity (PMID: 27435373).; SCV001338147: At least one publication reports experimental evidence evaluating an impact on protein function in-vitro. The most pronounced variant effect results in abrogation of mismatch repair (MMR) activity at levels identical to or lower than the repair-deficient control (van der Klift_2016). PMID: 29445031
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 7-6003724-G-A is Pathogenic according to our data. Variant chr7-6003724-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 127789.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.319C>T	p.Arg107Trp	missense	Exon 4 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406875.1		c.-166C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001393804.1
	PMS2	NM_001322015.2		c.-166C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001308944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.319C>T	p.Arg107Trp	missense	Exon 4 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.319C>T	p.Arg107Trp	missense	Exon 4 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.319C>T		non_coding_transcript_exon	Exon 4 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000127 AC: 3 AN: 236786 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000829 AC: 12 AN: 1446654 Hom.: 0 Cov.: 29 AF XY: 0.00000416 AC XY: 3 AN XY: 720294

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4950

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110372

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74408

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000843 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Lynch syndrome 4 (2)
2	-	-	not provided (2)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome (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	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MVP		0.97
MPC		0.28
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.012	Neutral
Varity_R		0.99
gMVP		0.92
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: -34

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

Other links and lift over

dbSNP: rs188006077; hg19: chr7-6043355; COSMIC: COSV56223415; COSMIC: COSV56223415;