chr2-47408400-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 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).

• 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: Likely_pathogenic. The variant received 9 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.
• 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;