2-47408400-G-T

Variant names:

• chr2-47408400-G-T
• rs267607914
• NM_000251.3:c.212-1G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PS3 PP5

The NM_000251.3(MSH2):​c.212-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005776615: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in activation of cryptic splice sites and introduces a premature termination codon (PMID:29568967).".

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.49
• Publications: 13 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 13 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: SCV005776615: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in activation of cryptic splice sites and introduces a premature termination codon (PMID: 29568967).
• PP5: Variant 2-47408400-G-T is Pathogenic according to our data. Variant chr2-47408400-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 801679.

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.212-1G>T		splice_acceptor intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.212-1G>T		splice_acceptor intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.212-1G>T		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.212-1G>T		splice_acceptor intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.212-1G>T		splice_acceptor intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.212-1G>T		splice_acceptor intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150806 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1449734 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721454

African (AFR) AF: 0.00 AC: 0 AN: 32778

American (AMR) AF: 0.00 AC: 0 AN: 43132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 84742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105294

Other (OTH) AF: 0.00 AC: 0 AN: 59842

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 150806 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73568

African (AFR) AF: 0.00 AC: 0 AN: 41014

American (AMR) AF: 0.00 AC: 0 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67764

Other (OTH) AF: 0.00 AC: 0 AN: 2068

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		8.5
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 9
DS_AL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs267607914; hg19: chr2-47635539;