7-5997425-T-C

Variant names:

• chr7-5997425-T-C
• rs745487791
• NM_000535.7:c.706-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000535.7(PMS2):​c.706-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000225 in 1,331,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: PMS2 NM_000535.7 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.68
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.7, offset of 8, new splice context is: tttttttttcggttgcaaAGcct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-5997425-T-C is Pathogenic according to our data. Variant chr7-5997425-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1172908.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.706-2A>G		splice_acceptor intron	N/A	NP_000526.2
	PMS2	NM_001406866.1		c.892-2A>G		splice_acceptor intron	N/A	NP_001393795.1
	PMS2	NM_001322014.2		c.706-2A>G		splice_acceptor 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.706-2A>G		splice_acceptor intron	N/A	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.706-2A>G		splice_acceptor intron	N/A	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.706-2A>G		splice_acceptor intron	N/A	ENSP00000514464.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.00000705 AC: 1 AN: 141916 AF XY: 0.0000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000161

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000225 AC: 3 AN: 1331160 Hom.: 0 Cov.: 22 AF XY: 0.00000450 AC XY: 3 AN XY: 666912

African (AFR) AF: 0.00 AC: 0 AN: 29602

American (AMR) AF: 0.00 AC: 0 AN: 37558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24560

East Asian (EAS) AF: 0.00 AC: 0 AN: 39014

South Asian (SAS) AF: 0.00 AC: 0 AN: 78762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.00000298 AC: 3 AN: 1007934

Other (OTH) AF: 0.00 AC: 0 AN: 55778

GnomAD4 genome Cov.: 27

ExAC AF: 0.00000844 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome 4 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		6.7
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -10
DS_AL_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745487791; hg19: chr7-6037056;