rs587779195

chr2-47414420-T-Achr2-47414420-T-Cchr2-47414420-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):c.942+2T>A variant causes a splice donor change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 2/2 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05311943 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	UniProt
MSH2	NM_000251.3	c.942+2T>A		splice_donor_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.942+2T>A		splice_donor_variant		1	NM_000251.3	P1

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 28, 2023	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]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 15, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 12, 2023	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 10, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 12, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu310) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 428474). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 24278394, 25980754). This variant is not present in population databases (gnomAD no frequency). 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. -

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
MutationTaster	Benign	1.0	D;D;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;