NM_000251.3:c.942+3A>C

Variant names:

• chr2-47414421-A-C
• rs193922376
• NM_000251.3:c.942+3A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PP3_Strong PP5

The NM_000251.3(MSH2):​c.942+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign 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: "SCV002683303: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data)." and additional evidence is available in ClinVar. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 0)
• Consequence: MSH2 NM_000251.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.32
• Publications: 0 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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002683303: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV004188173: Functional studies indicate this variant impacts protein function [PMID: 8062247].
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47414421-A-C is Pathogenic according to our data. Variant chr2-47414421-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1200813.

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.942+3A>C		splice_region intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.942+3A>C		splice_region intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+3A>C		splice_region 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.942+3A>C		splice_region intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.942+3A>C		splice_region intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.993+3A>C		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Lynch syndrome 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.68		Position offset: -3

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

Other links and lift over

dbSNP: rs193922376; hg19: chr2-47641560;