7-5997426-GAAAAAAA-GAAAA

Variant names:

• chr7-5997426-GAAA-G
• rs60794673
• NM_000535.7:c.706-6_706-4delTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000535.7(PMS2):​c.706-6_706-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,092,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000068 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0044 (0 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• 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

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 7-5997426-GAAA-G is Benign according to our data. Variant chr7-5997426-GAAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 286329.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.706-6_706-4delTTT		splice_region intron	N/A	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.892-6_892-4delTTT		splice_region intron	N/A	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.706-6_706-4delTTT		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.706-6_706-4delTTT		splice_region intron	N/A	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.706-6_706-4delTTT		splice_region intron	N/A	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.706-6_706-4delTTT		splice_region intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.0000676 AC: 9 AN: 133216 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000760

Gnomad ASJ AF: 0.000310

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000275

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000638

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00578 AC: 835 AN: 144514 AF XY: 0.00593

Gnomad AFR exome AF: 0.00780

Gnomad AMR exome AF: 0.00597

Gnomad ASJ exome AF: 0.00450

Gnomad EAS exome AF: 0.0101

Gnomad FIN exome AF: 0.00317

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00442 AC: 4243 AN: 958902 Hom.: 0 AF XY: 0.00432 AC XY: 2123 AN XY: 491112

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00611 AC: 135 AN: 22086

American (AMR) AF: 0.00456 AC: 147 AN: 32262

Ashkenazi Jewish (ASJ) AF: 0.00304 AC: 63 AN: 20754

East Asian (EAS) AF: 0.00550 AC: 182 AN: 33112

South Asian (SAS) AF: 0.00422 AC: 279 AN: 66062

European-Finnish (FIN) AF: 0.00171 AC: 83 AN: 48432

Middle Eastern (MID) AF: 0.00327 AC: 15 AN: 4586

European-Non Finnish (NFE) AF: 0.00459 AC: 3166 AN: 689056

Other (OTH) AF: 0.00407 AC: 173 AN: 42552

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000675 AC: 9 AN: 133258 Hom.: 0 Cov.: 0 AF XY: 0.0000784 AC XY: 5 AN XY: 63796

African (AFR) AF: 0.0000286 AC: 1 AN: 34980

American (AMR) AF: 0.0000759 AC: 1 AN: 13170

Ashkenazi Jewish (ASJ) AF: 0.000310 AC: 1 AN: 3224

East Asian (EAS) AF: 0.00 AC: 0 AN: 4710

South Asian (SAS) AF: 0.00 AC: 0 AN: 4224

European-Finnish (FIN) AF: 0.000275 AC: 2 AN: 7272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000638 AC: 4 AN: 62692

Other (OTH) AF: 0.00 AC: 0 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
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: COSV56223517; COSMIC: COSV56223517;