2-47480684-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000251.3(MSH2):​c.2459-12A>G variant causes a 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

MSH2
NM_000251.3 intron

Scores

2
Splicing: ADA: 0.5818
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: -0.423
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
PP5
Variant 2-47480684-A-G is Pathogenic according to our data. Variant chr2-47480684-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90977.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=1, Pathogenic=2}. Variant chr2-47480684-A-G is described in Lovd as [Likely_pathogenic]. Variant chr2-47480684-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.2459-12A>G intron_variant Intron 14 of 15 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkc.2459-12A>G intron_variant Intron 14 of 15 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary nonpolyposis colon cancer Pathogenic:2
Apr 26, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MSH2 c.2459-12A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes or weakens the canonical 3' acceptor site and four predict the variant creates novel a 3' acceptor site. Multiple publications report experimental evidence that this variant indeed affects mRNA splicing, creating a new 3' acceptor site which results in the insertion of 11 nucleotides, disrupting the reading frame and producing an abnormal transcript expected to undergo nonsense mediated decay (e.g. Fulk_2022, Morak_2022, Schwenk_2023). The variant was absent in 251254 control chromosomes. c.2459-12A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome, including those whose tumors exhibited high microsatellite instability and loss of MSH2 protein expression on IHC, and in at least one family who met Amsterdam II criteria (e.g. Mangold_2005, Barrow_2010, Fulk_2022, Morak_2022). These data indicate that the variant is likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20459533, 35487642, 16216036, 15849733, 35676339, 33383211, 36593122). ClinVar contains an entry for this variant (Variation ID: 90977). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 05, 2025
Mendelics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2459-12A>G (NM_000251.3) intronic variant results from an A to G substitution 12 nucleotides upstream from coding exon 15 in the MSH2 gene. It has been previously reported in individuals with clinical characteristics of Lynch syndrome, including tumors with high microsatellite instability and/or loss of MSH2 protein via immunohistochemistry analysis (PMID: 15849733, 16216036, 20459533, 35676339, 36593122). In silico analysis predicts that this alteration will weaken the native splice site. Functional RNA studies have shown that this variant causes abnormal splicing and results in an inclusion of 11bp and disruption of the reading frame (PMID: 35676339, 36593122). Therefore the available evidence suggests that this variant is likely to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2
May 02, 2024
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2459-12A>G intronic variant (also known as IVS14-12A>G) results from an A to G substitution 12 nucleotides upstream from coding exon 15 in the MSH2 gene. This alteration was identified in an individual whose colorectal tumor demonstrated loss of MSH2 protein expression on immunohistochemistry (IHC) and met Amsterdam II criteria for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Ambry internal data). This alteration was also observed in an individual whose colorectal tumor displayed high microsatellite instability (MSI-H) and loss of MSH2 protein expression on IHC (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Mangold E et al. J. Pathol., 2005 Dec;207:385-95). It was subsequently observed in another patient whose HNPCC/Lynch syndrome-related tumor showed loss of MSH2 protein expression on IHC (Barrow, E et al. Histopathology. 2010 Feb;56(3):331-44). This nucleotide position is highly conserved in available primates, but not well conserved in other available vertebrate species. 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. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Feb 23, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the -12 position of intron 14 of the MSH2 gene. RNA studies have shown that this variant causes the insertion of 11 nucleotides from intron 14 and disruption of the reading frame, resulting in premature truncation (PMID: 35676339, 36593122). This variant has been reported in more than five individuals affected with Lynch syndrome-associated cancers, with tumors from several individuals showing high microsatellite instability and/or loss of MSH2 protein via immunohistochemistry analysis (PMID: 15849733, 16216036, 20459533, 36457512, 35676339, 36593122). 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 Pathogenic. -

Lynch syndrome 1 Pathogenic:1
Aug 08, 2023
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -

Lynch syndrome Pathogenic:1
May 01, 2018
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MSH2 NM_000251.2:c.2459-12A>G has a 98.8% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56, 1.56, 1.56, 1.56, and 26.5 to 1, generated from evidence of seeing this as a somatic mutation in 5 independent tumors 4 of which did not have loss of heterozygosit and one of which had loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Feb 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 15849733, 16216036, 20459533, 35487642, 35676339; Invitae). ClinVar contains an entry for this variant (Variation ID: 90977). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 35487642, 35676339; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Pathogenic:1
May 14, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Sep 22, 2014
GeneDx
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

This variant is denoted MSH2 c.2459-12A>G or IVS14-12A>G and consists of an A>G nucleotide substitution at the -12 position of intron 14 of the MSH2 gene. Multiple in silico models predict this variant to damage the nearby natural acceptor site, and to possibly cause abnormal gene splicing. This variant was observed in an individual with either a personal or family history suggestive of Lynch syndrome (Mangold 2005). MSH2 c.2459-12A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available information, it is unclear whether MSH2 c.2459-12A>G is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
22
DANN
Benign
0.62
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.58
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.98
Position offset: 1
DS_AL_spliceai
0.73
Position offset: 12

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267608012; hg19: chr2-47707823; API