chr2-47470964-G-A

Variant names:

• chr2-47470964-G-A
• rs267607970
• NM_000251.3:c.1662-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.1662-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000731656: This variant has shown to cause exon 11 skipping in blood derived patient RNA and results in an absent MSH2 protein (Whiteside 2002)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.22
• Publications: 6 publications found

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000731656: This variant has shown to cause exon 11 skipping in blood derived patient RNA and results in an absent MSH2 protein (Whiteside 2002).; SCV001412155: Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11809679, 24090359).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47470964-G-A is Pathogenic according to our data. Variant chr2-47470964-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 90727.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. 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
	MSH2	NM_000251.3	MANE Select	c.1662-1G>A		splice_acceptor intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1662-1G>A		splice_acceptor intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1662-1G>A		splice_acceptor intron	N/A	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1662-1G>A		splice_acceptor intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1662-1G>A		splice_acceptor intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1713-1G>A		splice_acceptor intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1278470 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 645932

African (AFR) AF: 0.00 AC: 0 AN: 29890

American (AMR) AF: 0.00 AC: 0 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24954

East Asian (EAS) AF: 0.00 AC: 0 AN: 38642

South Asian (SAS) AF: 0.00 AC: 0 AN: 82146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 946202

Other (OTH) AF: 0.00 AC: 0 AN: 53998

GnomAD4 genome Cov.: 32

Alfa AF: 0.00173 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Lynch syndrome (2)
2	-	-	Lynch syndrome 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch-like syndrome (1)
1	-	-	Mismatch repair cancer syndrome 2 (1)
1	-	-	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.2
GERP RS		5.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs267607970; hg19: chr2-47698103; COSMIC: COSV108758012;