rs193922376

Positions:

• chr2-47414421-A-C
• chr2-47414421-A-G
• chr2-47414421-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_Strong PP5

The NM_000251.3(MSH2):​c.942+3A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: MSH2 NM_000251.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.32

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 Uncertain_significance. Variant got 5 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47414421-A-C is Pathogenic according to our data. Variant chr2-47414421-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1200813.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+3A>C		splice_donor_region_variant, intron_variant		ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.942+3A>C		splice_donor_region_variant, intron_variant		1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 28, 2023	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8062247]. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2021

Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2022

The c.942+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 5 in the MSH2 gene. This variant was identified in an individual whose early onset, MSI-H colon tumor demonstrated absent MSH2 and MSH6 by immunohistochemistry (IHC) along with a somatic pathogenic mutation in MSH2 (Ambry internal data). While this exact alteration has not been reported in the literature, an alteration at the same nucleotide position (c.942+3A>T) has been reported in numerous individuals meeting clinical diagnostic criteria for Lynch syndrome and has been shown by multiple functional studies to cause exon 5 skipping (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100(4):277-81; Desai DC et al. J. Med. Genet. 2000 Sep;37(9):646-52; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70; Auclair J et al. Hum. Mutat. 2006 Feb;27(2):145-54; Casey G et al. JAMA. 2005 Feb;293(7):799-809; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812). Furthermore, RNA studies have demonstrated a different alteration at this same position (c.942+3A>G) results in abnormal splicing as well (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change falls in intron 5 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1200813). 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. This variant disrupts the c.942+3 nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8062247, 10978353, 15222003, 16395668, 19419416, 20682701, 21681552, 22883484, 24310308). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.68		Position offset: -3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-47641560;