7-5986753-C-T

Variant names:

• chr7-5986753-C-T
• rs111905775
• NM_000535.7:c.2006+6G>A

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.2006+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,573,106 control chromosomes in the GnomAD database, including 5,348 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 0.052 (521 hom., cov: 32)
  • Exomes 𝑓: 0.056 (4827 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Scores: Splicing: ADA: 0.00007389
• Clinical Significance: Benign reviewed by expert panel B:18
• Conservation: PhyloP100: 0.219
• Publications: 13 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=-0.71).
• BP6: Variant 7-5986753-C-T is Benign according to our data. Variant chr7-5986753-C-T is described in ClinVar as Benign. ClinVar VariationId is 91324.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 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.2006+6G>A		splice_region intron	N/A	NP_000526.2
	PMS2	NM_001406866.1		c.2192+6G>A		splice_region intron	N/A	NP_001393795.1
	PMS2	NM_001322014.2		c.2006+6G>A		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.2006+6G>A		splice_region intron	N/A	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.804-3762G>A		intron	N/A	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.1678+334G>A		intron	N/A	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.0516 AC: 7834 AN: 151924 Hom.: 520 Cov.: 32

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0629

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0461

GnomAD2 exomes AF: 0.0760 AC: 17203 AN: 226258 AF XY: 0.0797

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0597

Gnomad EAS exome AF: 0.338

Gnomad FIN exome AF: 0.0866

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0559 AC: 79399 AN: 1421062 Hom.: 4827 Cov.: 28 AF XY: 0.0583 AC XY: 41171 AN XY: 706020

African (AFR) AF: 0.0160 AC: 504 AN: 31536

American (AMR) AF: 0.0224 AC: 840 AN: 37480

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 1581 AN: 24740

East Asian (EAS) AF: 0.352 AC: 13766 AN: 39054

South Asian (SAS) AF: 0.143 AC: 11021 AN: 76986

European-Finnish (FIN) AF: 0.0877 AC: 4594 AN: 52360

Middle Eastern (MID) AF: 0.0492 AC: 201 AN: 4084

European-Non Finnish (NFE) AF: 0.0392 AC: 42945 AN: 1096356

Other (OTH) AF: 0.0675 AC: 3947 AN: 58466

GnomAD4 genome AF: 0.0516 AC: 7840 AN: 152044 Hom.: 521 Cov.: 32 AF XY: 0.0559 AC XY: 4157 AN XY: 74328

African (AFR) AF: 0.0175 AC: 728 AN: 41508

American (AMR) AF: 0.0323 AC: 493 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 218 AN: 3466

East Asian (EAS) AF: 0.338 AC: 1745 AN: 5160

South Asian (SAS) AF: 0.159 AC: 767 AN: 4824

European-Finnish (FIN) AF: 0.0875 AC: 923 AN: 10546

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0417 AC: 2831 AN: 67970

Other (OTH) AF: 0.0523 AC: 110 AN: 2104

Alfa AF: 0.0431 Hom.: 70

Bravo AF: 0.0440

Asia WGS AF: 0.248 AC: 860 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Lynch syndrome 4 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Lynch 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	-0.71
CADD	Benign	10
DANN	Benign	0.56
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.0020
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: rs111905775; hg19: chr7-6026384; COSMIC: COSV56219357;