chr7-6003717-T-TC

Variant names:

• chr7-6003717-T-TC
• rs587781716
• NM_000535.7:c.325dupG

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000535.7(PMS2):​c.325dupG​(p.Glu109GlyfsTer30) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 151,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000625635: Studies have shown that this premature translational stop signal alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:26247049).". Synonymous variant affecting the same amino acid position (i.e. E109E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.30
• Publications: 12 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000625635: Studies have shown that this premature translational stop signal alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-6003717-T-TC is Pathogenic according to our data. Variant chr7-6003717-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 233300.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.325dupG	p.Glu109GlyfsTer30	frameshift	Exon 4 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.511dupG	p.Glu171GlyfsTer30	frameshift	Exon 5 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.325dupG	p.Glu109GlyfsTer30	frameshift	Exon 4 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.325dupG	p.Glu109GlyfsTer30	frameshift	Exon 4 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.325dupG	p.Glu109GlyfsTer30	frameshift	Exon 4 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.325dupG		non_coding_transcript_exon	Exon 4 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151980 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: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000169 AC: 4 AN: 236098 AF XY: 0.0000231

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: 0.00000917

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000485 AC: 7 AN: 1443120 Hom.: 0 Cov.: 29 AF XY: 0.00000557 AC XY: 4 AN XY: 718708

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4786

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1108014

Other (OTH) AF: 0.0000167 AC: 1 AN: 60004

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151980 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Lynch syndrome 4 (4)
3	-	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587781716; hg19: chr7-6043348;