7-5997426-GAAAAAAA-GAAAAA

Variant names:

• chr7-5997426-GAA-G
• rs60794673
• NM_000535.7:c.706-5_706-4delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000535.7(PMS2):​c.706-5_706-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 1,068,662 control chromosomes in the GnomAD database, including 16 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (13 hom., cov: 0)
  • Exomes 𝑓: 0.067 (3 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• 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 -16 ACMG points.

• BP6: Variant 7-5997426-GAA-G is Benign according to our data. Variant chr7-5997426-GAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00967 (1288/133228) while in subpopulation AFR AF = 0.0323 (1128/34976). AF 95% confidence interval is 0.0307. There are 13 homozygotes in GnomAd4. There are 598 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.706-5_706-4delTT		splice_region intron	N/A	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.892-5_892-4delTT		splice_region intron	N/A	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.706-5_706-4delTT		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.706-5_706-4delTT		splice_region intron	N/A	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.706-5_706-4delTT		splice_region intron	N/A	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.706-5_706-4delTT		splice_region intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1288 AN: 133186 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.0323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00418

Gnomad ASJ AF: 0.000931

Gnomad EAS AF: 0.000424

Gnomad SAS AF: 0.00259

Gnomad FIN AF: 0.00468

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000734

Gnomad OTH AF: 0.00487

GnomAD2 exomes AF: 0.102 AC: 14756 AN: 144514 AF XY: 0.102

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0809

Gnomad ASJ exome AF: 0.0874

Gnomad EAS exome AF: 0.185

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0950

GnomAD4 exome AF: 0.0672 AC: 62887 AN: 935434 Hom.: 3 AF XY: 0.0675 AC XY: 32283 AN XY: 478002

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

African (AFR) AF: 0.0735 AC: 1588 AN: 21600

American (AMR) AF: 0.0734 AC: 2310 AN: 31470

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 1450 AN: 20046

East Asian (EAS) AF: 0.146 AC: 4508 AN: 30790

South Asian (SAS) AF: 0.0731 AC: 4668 AN: 63816

European-Finnish (FIN) AF: 0.0553 AC: 2571 AN: 46490

Middle Eastern (MID) AF: 0.0653 AC: 285 AN: 4364

European-Non Finnish (NFE) AF: 0.0632 AC: 42693 AN: 675478

Other (OTH) AF: 0.0680 AC: 2814 AN: 41380

⚠️ 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: 0.00967 AC: 1288 AN: 133228 Hom.: 13 Cov.: 0 AF XY: 0.00938 AC XY: 598 AN XY: 63780

African (AFR) AF: 0.0323 AC: 1128 AN: 34976

American (AMR) AF: 0.00417 AC: 55 AN: 13176

Ashkenazi Jewish (ASJ) AF: 0.000931 AC: 3 AN: 3224

East Asian (EAS) AF: 0.000425 AC: 2 AN: 4706

South Asian (SAS) AF: 0.00260 AC: 11 AN: 4224

European-Finnish (FIN) AF: 0.00468 AC: 34 AN: 7260

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

European-Non Finnish (NFE) AF: 0.000734 AC: 46 AN: 62678

Other (OTH) AF: 0.00484 AC: 9 AN: 1860

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)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Lynch syndrome 4 (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)
-	-	1	not provided (1)
-	-	1	PMS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

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: COSV56224728; COSMIC: COSV56224728;