2-47480684-A-G

Variant names:

• chr2-47480684-A-G
• rs267608012
• NM_000251.3:c.2459-12A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 intron
• Scores: Splicing: ADA: 0.5818
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: -0.423
• Publications: 6 publications found

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]

MSH2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 90977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.2459-12A>G		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.2459-12A>G		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.2459-12A>G		intron	N/A	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.2459-12A>G		intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.2459-12A>G		intron	N/A	ENSP00000384199.1
	MSH2	ENST00000713867.1		n.*300A>G		non_coding_transcript_exon	Exon 15 of 16	ENSP00000519172.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colon cancer Pathogenic:2

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.

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.

Hereditary cancer-predisposing syndrome Pathogenic:2

May 05, 2025

Ambry Genetics

Significance: 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 supporting evidence, this variant is interpreted as a disease-causing mutation.

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	22
DANN	Benign	0.62
PhyloP100		-0.42
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
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs267608012; hg19: chr2-47707823;