NM_000535.7:c.2007-7C>T

Variant names:

• chr7-5982998-G-A
• rs55954143
• NM_000535.7:c.2007-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.2007-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,409,502 control chromosomes in the GnomAD database, including 4,466 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1391 hom., cov: 31)
  • Exomes 𝑓: 0.068 (3075 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Scores: Splicing: ADA: 0.00002982
• Clinical Significance: Benign reviewed by expert panel B:20
• Conservation: PhyloP100: 0.672
• Publications: 11 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: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-5982998-G-A is Benign according to our data. Variant chr7-5982998-G-A is described in ClinVar as Benign. ClinVar VariationId is 36687.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.2007-7C>T		splice_region intron	N/A	NP_000526.2
	PMS2	NM_001406866.1		c.2193-7C>T		splice_region intron	N/A	NP_001393795.1
	PMS2	NM_001322014.2		c.2007-7C>T		splice_region intron	N/A	NP_001308943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2007-7C>T		splice_region intron	N/A	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.804-7C>T		splice_region intron	N/A	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.1678+4089C>T		intron	N/A	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17653 AN: 150504 Hom.: 1379 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.0876

Gnomad SAS AF: 0.0897

Gnomad FIN AF: 0.0908

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0951

GnomAD2 exomes AF: 0.0758 AC: 11269 AN: 148764 AF XY: 0.0743

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.0885

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0662

Gnomad OTH exome AF: 0.0621

GnomAD4 exome AF: 0.0684 AC: 86153 AN: 1258874 Hom.: 3075 Cov.: 18 AF XY: 0.0688 AC XY: 43227 AN XY: 628484

African (AFR) AF: 0.240 AC: 6519 AN: 27124

American (AMR) AF: 0.0356 AC: 1249 AN: 35080

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 959 AN: 24266

East Asian (EAS) AF: 0.0828 AC: 2960 AN: 35746

South Asian (SAS) AF: 0.0845 AC: 6467 AN: 76514

European-Finnish (FIN) AF: 0.0928 AC: 4628 AN: 49846

Middle Eastern (MID) AF: 0.0554 AC: 222 AN: 4004

European-Non Finnish (NFE) AF: 0.0620 AC: 59128 AN: 953476

Other (OTH) AF: 0.0761 AC: 4021 AN: 52818

GnomAD4 genome AF: 0.117 AC: 17693 AN: 150628 Hom.: 1391 Cov.: 31 AF XY: 0.118 AC XY: 8655 AN XY: 73644

African (AFR) AF: 0.245 AC: 9870 AN: 40272

American (AMR) AF: 0.0596 AC: 905 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3468

East Asian (EAS) AF: 0.0877 AC: 453 AN: 5168

South Asian (SAS) AF: 0.0890 AC: 427 AN: 4800

European-Finnish (FIN) AF: 0.0908 AC: 953 AN: 10496

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0688 AC: 4676 AN: 67938

Other (OTH) AF: 0.0941 AC: 197 AN: 2094

Alfa AF: 0.0808 Hom.: 207

Bravo AF: 0.123

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Lynch syndrome 4 (5)
-	-	3	Lynch syndrome (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Endometrial carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.7
DANN	Benign	0.55
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0040
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: rs55954143; hg19: chr7-6022629;