rs587779195

Variant names:

• chr2-47414420-T-A
• rs587779195
• NM_000251.3:c.942+2T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47414420-T-A
• chr2-47414420-T-C
• chr2-47414420-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000251.3(MSH2):​c.942+2T>A variant causes a splice donor, 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 11)
  • Exomes 𝑓: 0.0000071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.70

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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.053475935 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 2-47414420-T-A is Pathogenic according to our data. Variant chr2-47414420-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47414420-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+2T>A		splice_donor_variant, intron_variant	Intron 5 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.942+2T>A		splice_donor_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 60 AN: 62212 Hom.: 0 Cov.: 11 FAILED QC

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000242

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000684

Gnomad OTH AF: 0.00386

GnomAD4 exome AF: 0.00000713 AC: 7 AN: 982170 Hom.: 0 Cov.: 18 AF XY: 0.00000615 AC XY: 3 AN XY: 488162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000535

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000932

Gnomad4 NFE exome AF: 0.00000383

Gnomad4 OTH exome AF: 0.0000259

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000964 AC: 60 AN: 62212 Hom.: 0 Cov.: 11 AF XY: 0.00102 AC XY: 28 AN XY: 27556

Gnomad4 AFR AF: 0.00155

Gnomad4 AMR AF: 0.000242

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00315

Gnomad4 NFE AF: 0.000684

Gnomad4 OTH AF: 0.00386

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Nov 07, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong, PM2_Supporting, PP4_Strong c.942+2T>A, located in a canonic splicing site of the MSH2 is predicted to alter splicing, probably causing the skipping of exon 5. This alteration is expected to preserve reading frame and the altered region is critical to protein function (PVS1_Strong).It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_Supporting). It has been reported in multiple patients with Lynch syndrome suspicion (PMID: 21239990, 24278394, 25980754, 33630411, 36091691, internal data), at least five of them were confirmed endometrial and/or colorectal cancer-affected patients with loss of MSH2/MSH6 expression by IHC (PMID: 21239990, 36091691 and 33630411, and internal data from our cohort) (PP4_Strong). This variant has been reported in ClinVar database (4x pathogenic, 2x likely pathogenic) and LOVD (5x pathogenic), and classified by InSiGHT as pathogenic. Based on currently available information, the variant c.942+2T>A should be considered a likely pathogenic variant, according to MMR-specific InSIGHT Guidelines, Draft v3.1. -

Oct 12, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.942+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 5 in the MSH2 gene. This mutation has been reported in multiple individuals with Lynch syndrome-associate cancers who met Amsterdam I or II criteria or Bethesda Guidelines and whose tumors were MSI-H and showed absence of MSH2 on immunohistochemistry (de Lellis L at al. PLoS ONE 2013;8(11):e81194; Castillejo MI et al. eJIFCC Volume 27 no 1; February 2016). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Mar 23, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a T to A nucleotide substitution at the +2 position of intron 5 of the MSH2 gene. This variant is found adjacent to a poly-adenosine sequence, where the precise number of adenosine is difficult to determine via conventional sequencing technologies. Therefore, this variant may be reported by external laboratories as a deletion encompassing the +2T and varying number of adenosine, e.g. c.942+2del (ClinVar variation ID 91250) and c.942+2_942+6del (ClinVar variation ID 237416). All such variants are predicted to have the same splicing impact. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to disrupt the DNA binding domain of the MSH2 protein. This variant has been reported in an individual affected with Lynch syndrome–associated cancer and/or polyps (PMID: 25980754). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Lynch syndrome 1 Pathogenic:2

Jul 28, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. Functional studies indicate this variant impacts protein function [PMID: 8062247]. -

Jan 15, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 10, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in a canonical splice-donor site and interferes with normal MSH2 mRNA splicing. The variant has been reported in individuals with Lynch syndrome-associated cancer and/or polyps in the published literature (PMIDs: 21239990 (2011), 24278394 (2013), 25980754 (2015), and 33630411 (2021)). In addition, tumors of individuals with this variant were MSI-H and showed absence of MSH2 protein on immunohistochemistry (PMIDs: 24278394 (2013) and 33630411 (2021)). Therefore, the variant is classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 5 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 24278394, 25980754). ClinVar contains an entry for this variant (Variation ID: 428474). Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (internal data). This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu310) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779195; hg19: chr2-47641559;