rs63751624

Variant names:

• chr2-47480871-G-A
• rs63751624
• NM_000251.3:c.2634G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47480871-G-A
• chr2-47480871-G-C
• chr2-47480871-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2634G>A​(p.Glu878Glu) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000580401: This alteration has been identified in several individuals with Lynch syndrome-associated tumors demonstrating absent MSH2/MSH6 staining by IHC analysis and family histories meeting Amsterdam criteria (Ambry Internal Data). This mutation was reported in a Spanish woman with a MSI-H endometrial cancer that demonstrated absent MSH2 staining by IHC analysis" and additional evidence is available in ClinVar. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.65
• Publications: 7 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000580401: This alteration has been identified in several individuals with Lynch syndrome-associated tumors demonstrating absent MSH2/MSH6 staining by IHC analysis and family histories meeting Amsterdam criteria (Ambry Internal Data). This mutation was reported in a Spanish woman with a MSI-H endometrial cancer that demonstrated absent MSH2 staining by IHC analysis; her family history met Amsterdam criteria. Authors subsequently used mRNA analysis to demonstrate that this alteration results in skipping of exon 15 (Pérez-Cabornero L et al. Cancer Prev Res (Phila), 2011 Oct;4:1546-55; Pérez-Cabornero L et al. J Mol Diagn, 2013 May;15:380-90).; SCV000260754: Studies have shown that this variant results in skipping of exon 15, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23523604).; SCV001431962: The variant was reported to affect mRNA splicing by skipping on exon 15 (Perez-Cabornero_2013).
• PM2: Very rare variant in population databases, with high coverage
• 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 2-47480871-G-A is Pathogenic according to our data. Variant chr2-47480871-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 91021.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.2634G>A	p.Glu878Glu	splice_region synonymous	Exon 15 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.2634G>A	p.Glu878Glu	splice_region synonymous	Exon 15 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.2634G>A	p.Glu878Glu	splice_region synonymous	Exon 15 of 18	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.2634G>A	p.Glu878Glu	splice_region synonymous	Exon 15 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.2634G>A	p.Glu878Glu	splice_region synonymous	Exon 15 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.2685G>A	p.Glu895Glu	splice_region synonymous	Exon 16 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000217 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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 (1)
1	-	-	Lynch syndrome 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.92
PhyloP100		8.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: 0

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

Other links and lift over

dbSNP: rs63751624; hg19: chr2-47708010;