7-5997426-GAAAAAAA-GAAAAAA

Variant names:

• chr7-5997426-GA-G
• rs60794673
• NM_000535.7:c.706-4delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.706-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.45 (12592 hom., cov: 0)
  • Exomes 𝑓: 0.40 (4732 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: 0.187
• Publications: 10 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-5997426-GA-G is Benign according to our data. Variant chr7-5997426-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

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.706-4delT		splice_region intron	N/A	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.892-4delT		splice_region intron	N/A	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.706-4delT		splice_region intron	N/A	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.706-4delT		splice_region intron	N/A	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.706-4delT		splice_region intron	N/A	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.706-4delT		splice_region intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.447 AC: 59543 AN: 133062 Hom.: 12589 Cov.: 0

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.517

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.453

GnomAD2 exomes AF: 0.431 AC: 62259 AN: 144514 AF XY: 0.432

Gnomad AFR exome AF: 0.397

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.464

Gnomad FIN exome AF: 0.436

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.435

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.400 AC: 377828 AN: 944554 Hom.: 4732 Cov.: 0 AF XY: 0.403 AC XY: 194409 AN XY: 482870

African (AFR) AF: 0.348 AC: 7428 AN: 21370

American (AMR) AF: 0.386 AC: 12206 AN: 31612

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 8875 AN: 20378

East Asian (EAS) AF: 0.475 AC: 15870 AN: 33442

South Asian (SAS) AF: 0.426 AC: 27345 AN: 64208

European-Finnish (FIN) AF: 0.414 AC: 19210 AN: 46356

Middle Eastern (MID) AF: 0.453 AC: 2019 AN: 4454

European-Non Finnish (NFE) AF: 0.393 AC: 267899 AN: 680922

Other (OTH) AF: 0.406 AC: 16976 AN: 41812

GnomAD4 genome AF: 0.448 AC: 59567 AN: 133100 Hom.: 12592 Cov.: 0 AF XY: 0.449 AC XY: 28627 AN XY: 63714

African (AFR) AF: 0.339 AC: 11838 AN: 34936

American (AMR) AF: 0.456 AC: 5994 AN: 13152

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1688 AN: 3222

East Asian (EAS) AF: 0.705 AC: 3319 AN: 4706

South Asian (SAS) AF: 0.536 AC: 2264 AN: 4224

European-Finnish (FIN) AF: 0.463 AC: 3371 AN: 7276

Middle Eastern (MID) AF: 0.511 AC: 136 AN: 266

European-Non Finnish (NFE) AF: 0.475 AC: 29749 AN: 62598

Other (OTH) AF: 0.455 AC: 847 AN: 1862

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	1	4	Lynch syndrome 4 (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Lynch syndrome (2)
-	-	2	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs60794673; hg19: chr7-6037057; COSMIC: COSV56220865; COSMIC: COSV56220865;