rs587779193

Variant names:

• chr2-47414419-G-A
• rs587779193
• NM_000251.3:c.942+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47414419-G-A
• chr2-47414419-G-C
• chr2-47414419-G-T

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.942+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: MSH2 NM_000251.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.59

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 0.053475935 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47414419-G-A is Pathogenic according to our data. Variant chr2-47414419-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 823244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47414419-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-47414419-G-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+1G>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+1G>A		splice_donor_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

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]. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Mar 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 823244). 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). 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. For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18566915, 21520333). 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 29, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.942+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the MSH2 gene. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
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: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779193; hg19: chr2-47641558;