7-5978622-C-T

Variant names:

• chr7-5978622-C-T
• rs587779337
• NM_000535.7:c.2249G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PS3 PP3_Strong PP5 BS2

The NM_000535.7(PMS2):​c.2249G>A​(p.Gly750Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,603,354 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000592948: In functional studies, the variant was demonstrated to reduce mismatch repair activity (Drost 2013, Shuen 2019)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G750V) has been classified as Uncertain significance. The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (2 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:2
• Conservation: PhyloP100: 7.36
• Publications: 18 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: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000592948: In functional studies, the variant was demonstrated to reduce mismatch repair activity (Drost 2013, Shuen 2019).; SCV000172925: Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in protein structural stability (Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr; 20(4):461-8).; SCV004359029: Functional studies have shown that this variant protein partially reduces DNA mismatch repair activity compared with wild type protein in in vitro-based assays (PMID: 24027009, 26116798, 30608896).; SCV000149588: Published functional studies demonstrate a damaging effect: reduced, though not deficient, MMR activity (PMID: 24027009, 30608896); SCV006325476: Functional studies indicate that this sequence change impacts PMS2 function, however, one of these studies suggested that this sequence change may have an intermediate effect on repair efficiency, indicating it may be pathogenic with reduced penetrance (PMID: 24027009, 26116798).; SCV000551998: Experimental studies have shown that this missense change affects PMS2 function (PMID: 24027009, 26116798).; SCV004187598: Functional studies indicate this variant impacts protein function [PMID: 30608896, 24027009].; SCV002555672: Experimental studies have shown that the variant compromises mismatch repair efficiency (e.g., Drost_PMS2_2013, Bodo_2015). PMID: 26116798, 34371384, 24027009, 35223509, 25856668, 26318770, 28888541, 18602922, 30608896.; SCV004111783: Functional studies have shown that this variant impacts protein function (Drost et al. 2013. PubMed ID: 24027009; Table A2, Shuen et al. 2019. PubMed ID: 30608896).; SCV005374647: Drost et al. 2013, PMID: 24027009
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-5978622-C-T is Pathogenic according to our data. Variant chr7-5978622-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 91334.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.2249G>A	p.Gly750Asp	missense	Exon 13 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.2435G>A	p.Gly812Asp	missense	Exon 14 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.2249G>A	p.Gly750Asp	missense	Exon 13 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.2249G>A	p.Gly750Asp	missense	Exon 13 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.1046G>A	p.Gly349Asp	missense	Exon 9 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.1679-908G>A		intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150300 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249726 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1453054 Hom.: 2 Cov.: 31 AF XY: 0.0000180 AC XY: 13 AN XY: 722800

African (AFR) AF: 0.00 AC: 0 AN: 33158

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.00 AC: 0 AN: 85844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000226 AC: 25 AN: 1105616

Other (OTH) AF: 0.0000167 AC: 1 AN: 59956

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150300 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73292

African (AFR) AF: 0.00 AC: 0 AN: 40578

American (AMR) AF: 0.00 AC: 0 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10390

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67564

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	not provided (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
3	-	-	Lynch syndrome 4 (3)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Inherited polyposis and early onset colorectal cancer - germline testing (1)
1	-	-	PMS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
PhyloP100		7.4
Varity_R		0.98
gMVP		0.89
Mutation Taster		=0/100	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

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

Other links and lift over

dbSNP: rs587779337; hg19: chr7-6018253;