2-47480693-T-G

Position:

• chr2-47480693-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000251.3(MSH2):​c.2459-3T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9827
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.332

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2459-3T>G		splice_region_variant, splice_polypyrimidine_tract_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.2459-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2022

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. 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: 525652). This variant has been observed in individual(s) with MSH2-related conditions (PMID: 10612827). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2023

The c.2459-3T>G intronic variant results from a T to G substitution 3 nucleotides upstream from coding exon 15 in the MSH2 gene. This nucleotide position is not well conserved in available vertebrate species. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and weak expression of MSH6 by immunohistochemistry (Meulemans L et al. J Med Genet, 2023 May;60:450-459). In the same study, the effect of the c.2459-3T>G variant on splicing was analyzed using a minigene assay, which generated three aberrant transcripts due to the weakening of the native acceptor site and the use of a downstream and upstream cryptic acceptor site (Meulemans L et al. J Med Genet, 2023 May;60:450-459). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	21
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.65		Position offset: 1
DS_AL_spliceai		0.83		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587781988; hg19: chr2-47707832;