rs1064792951

Variant names:

• chr2-47482780-AAGGTGAAAAAATTATTC-A
• rs1064792951
• NM_000251.3:c.2640_2656delTGAAAAAATTATTCAGG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.2640_2656delTGAAAAAATTATTCAGG​(p.Glu881ValfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47482780-AAGGTGAAAAAATTATTC-A is Pathogenic according to our data. Variant chr2-47482780-AAGGTGAAAAAATTATTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 408510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2640_2656delTGAAAAAATTATTCAGG	p.Glu881ValfsTer12	frameshift_variant	Exon 16 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2640_2656delTGAAAAAATTATTCAGG	p.Glu881ValfsTer12	frameshift_variant	Exon 16 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jul 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant is expected to disrupt nearly the entire C-terminal portion of the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain (disrupted residues Glu881-Thr934) (PMID: 9774676, 18822302, 17531815). Although functional studies have not been done for this particular variant, loss of the C-terminal region of the protein likely impairs MSH2 function (PMID: 9774676, 18822302, 17531815). This suggests that deletion of this region of the MSH2 protein is causative of disease. This sequence change results in a premature translational stop signal in the MSH2 gene (p.Glu881Valfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acids of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 408510). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2640_2656del17 pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a deletion of 17 nucleotides at nucleotide positions 2640 to 2656, causing a translational frameshift with a predicted alternate stop codon (p.E881Vfs*12). This alteration occurs at the 3' terminus of MSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 5.67% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064792951; hg19: chr2-47709919;