rs587779125

Positions:

• chr2-47475267-ACTGGTAAAAAAC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.2005+3_2005+14del variant causes a splice donor, splice donor 5th base, coding sequence, intron 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 9.28

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08734403 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 19, new splice context is: gggGTaacg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47475267-ACTGGTAAAAAAC-A is Pathogenic according to our data. Variant chr2-47475267-ACTGGTAAAAAAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475267-ACTGGTAAAAAAC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2005+3_2005+14del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	12/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2005+3_2005+14del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	12/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carcinoma of colon Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The MSH2 c.2005+3_2005+14del variant was identified in 2 of 354 proband chromosomes (frequency: 0.006) from individuals or families with Lynch Syndrome (Sanchez 2006, De Lellis 2013). The variant was also identified in dbSNP (ID: rs587779125) as “With Likely pathogenic allele”, Clinvitae database (classified as uncertain significance and likely pathogenic by ClinVar), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as uncertain significance by InSight, Mayo clinic; classified as likely pathogenic by Ambry Genetics). The variant was not identified in COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database, UMD, the genome Aggregation Database, the Exome Aggregation Consortium database. The c.2005+3_2005+14del variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In addition, the variant was found in two patients with Lynch Syndrome and with MSI-H and MMR defective IHC (Sanchez 2006, De Lellis 2013). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 90842). This variant is also known as 2003del12. This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 16288214, 24278394, 27273229, 33414168; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 12 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. It affects a nucleotide within the consensus splice site. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2020

The c.2005+3_2005+14del12 intronic variant results from a deletion of 12 nucleotides within intron 12 of the MSH2 gene. This variant has been reported in multiple individuals meeting either Amsterdam I or II criteria and their Lynch syndrome associated tumors demonstrated high microsatellite instability (MSI-H) and/or loss of MSH2 staining on immunohistochemistry (IHC) (De Lellis L et al. PLoS ONE 2013 ; 8(11):e81194; Ambry internal data). This variant was also reported in a patient diagnosed with colorectal cancer at age 51 whose tumor was MSI-H and had absent MSH2/MSH6 staining on IHC (Buchanan DD et al. J. Gastroenterol. Hepatol. 2017 Feb;32(2):427-438). These nucleotide positions are generally not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Mayo Clinic Laboratories, Mayo Clinic

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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: rs587779125; hg19: chr2-47702406;